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New Q: 15q11.2: Why do the symptoms of 15q11.2 deletion vary so much from person to person?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:


  This is a very good question. I wish I could give the exact answer, but I can give only my own explanation (which may not necessarily be correct).
 
  Del 15q11.2 is found in a relatively large percentage of patients with various neuropsychological phenotypes (schizophrenia, epilepsy, delay in intellectual development etc.). There is no doubt that this deletion is a RISK FACTOR for all these conditions. But a risk factor does not mean that everybody with this deletion will be affected. We have many similar situations. For example, smoking is a strong risk factor for lung cancer, but most smokers will not have this disorder in their lifetime. Or a purely genetic example - deletion 1q21.1 is a risk factor for TAR syndrome, but this disease will occur only if del 1q21.1 is associated with some genetic changes in RBM8A subunit - basically  an "innocent" part of DNA. 
 
  I think we have a similar situation in del 15q11.2 which may require some additional factors for the realization of genetic susceptibility into disease. Currently, we do not know these factors, and we do not even know whether these factors are withing 15q11.2 or outside. I hope, however, that all (or at least some) of these factors will be revealed in the near future, so it will be possible to predict the status of every fetus or every person having this deletion.

New Q: 5q15->q31.1: Results of a chromosome analysis show mosaicism for a deletion 5q15->q31.1. A follow-up microarray is recommended to rule out this etiology which is associated with reproductive risk and an increased risk of colon cancer risk.  Any information would help.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

Original Question:

 

  I recently had chromosome analysis completed for potential reproductive issues. The results showed: MOSAIC INTERSTITIAL DELETION OF 5Q GTG banded cytogenetic analysis of PHA stimulated cultures has revealed mosaicism for a deletion 5q15->q31.1. A follow-up microarray is recommended to rule out this type of correction etiology which is associated with reproductive risk. The array can also identify the specific gene loss which appears to include the APC tumor suppressor gene associated with colon cancer risk when deleted or mutated. If this is a germ line deletion, the cancer risk would be higher. The effects of mosaic alterations are highly variable, generally being attributed to the distribution in critical tissues, but effects are also related to the time during development in which the imbalance initiated. Any information would be helpful.

 

Answer:


  The patient, an apparently healthy man, has two cell lines: normal 46,XY and abnormal 46,XY, del(5)(q15q31.1). It is obvious that the normal cell line could not arise from the abnormal, but an abnormal line definitely arose from the normal. We do not know whether the abnormal line exists also in testicular tissue. Although the probability of del(5)(q15q31.1) in the gonads is very low, it cannot be completely excluded.
 
  If the line 46,XY,del(5)(q15q31.1) exists in the gonads the patient may produce sperm cells with a del(5)(q15q31.1). The fertilization of the normal egg-cell by such a sperm will cause the birth of the child with del(5)(q15q31.1) - a condition accompanied by multiple congenital anomalies and developmental delay.
 
  If the person is interested in having his own children there are two options:
 
  a) prenatal diagnosis of the fetal karyotype via amniocentesis to exclude del(5) in the fetus;
 
  b) testing of the sperm cells which will be used for fertilization [this way is technically more complicated and much more expensive]
 
  In summary, amniocentesis (the results of which we now know are currently pending) is recommended to rule out any chromosomal pathology in the fetus. The chances that you have an abnormal line in the gonadal tissues are low, but significant enough for prenatal testing.  If the test does show a chromosomal disorder, CDO can help with information. It is probably best though to wait for the results.
 
  With regard to any personal health impacts from this mosaic deletion, it will depend on the distribution of the abnormal cell line in different tissues. If the colonic epithelium (cells inside the colon) have this clone it may increase the risk of colonic polyps and cancer. However, I do not know how to find the exact karyotype of the colonic cells. Most likely the recommendation will be to have repeated colonoscopies (the same regimen which is used for asymptomatic persons having the APC mutation). I also recommend contacting a GI-doctor who has a better knowledge of this regimen.

 


New Q: arr[hg19] 1q21.1(145,390,156-145,888,926)x3: I would kindly ask for your experience and knowledge regarding the above CMA test results obtained during the 13th Week of our first pregnancy: What should we expect? What do statistics say? What are the current recommendations in this case?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:


  Most duplications of this kind are innocent familial variants. I recommend testing of both parents. If one of them is found to be a carrier we will have all reasons to consider this duplication as innocent. If however the duplication is sporadic it may increase the probability of some abnormalities in the fetus (or more likely in a child).

Q: t(17;22)(p11.2;q11.2): I'm a balanced translocation carrier: (17,22)(11.2p, 11.2q). I'm 8 weeks pregnant. Can you estimate what the chances would be of carrying a baby with an unbalanced translocation past 12 weeks? Thank you.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

 

Translocation t(17;22)(p11.2;q11.2).

 

Alternative segregation 2:2 may produce two types of unbalanced gametes:

 

1) der(17)t(17;22)(p11.2;q11.2) - deletion 17p11.2pter in association with excess 22q11.2qter. Such variant is almost incompatible with survival past 12 weeks.

 

2) der(22)t(17;22)(p11.2q11.2) - deletion 22q11.2qter in association with excess  17p11.2pter. Such embryo may survive until 12 weeks with a probability of 10-15%, but most likely could not survive till birth.

 

However when a translocation involves small acrocentric chromosomes we can expect 3:1 segregation. Such gamete will have an additional chromosome consisting of a piece of 22 (22pter-cen-q11.2) and a piece of 17 (p11.2pter). The embryo having such an imbalance will survive until birth. 

 

The total probability of an unbalanced fetus in the female carrier of such a translocation at 12 weeks is ~ 8-10%. In my opinion prenatal diagnosis is recommended.


Q: 1;7 balanced translocation - repeated miscarriages?

Although it is not possible for us to comment directly on any person's medical care (for example, I can't assume that your miscarriages were all due to unbalanced chromosomes 1 or 7), I can certainly provide you with general information about the risks of a balanced translocation.
In theory, there is a 25% chance with each pregnancy that a balanced 1;7 translocation carrier will transmit, in the egg or sperm depending on the person's sex, a normal copy of chromosome 1, and a normal copy of chromosome 7. This would result in the child having normal chromosomes. Likewise, there is an additional 25% chance that the child would inherit the same balanced chromosome translocation that the parent has. Thus, in theory, there should be at least a 50% chance that a person with a balanced translocation would have a pregnancy that is unaffected by an unbalanced translocation (which typically but not always causes miscarriage).
It is important to remember that the baseline risk of miscarriage is high (about 25-33%), in all women, regardless of balanced translocations. Thus, it would not be correct to assume that normal chromosomes 1 and 7 equates to a normal pregnancy.
I certainly wish you the best in your efforts to conceive a child, and trust that your geneticist will explain the findings in greater detail, and answer your questions. As always, please feel free to contact CDO with any concerns.
Thomas Morgan MD
Medical Geneticist

Q: 100% skewed X inactivation - Xq26.3 deletion Is it possible to look more closely at the active x for mutations?

There are a number of atypical features in your daughter. While terminal Xq deletions do cause skewed X inactivation, they are not to my knowledge associated with GH deficiency, hypoglycemia, or immunodeficiency. Skewing in and of itself is not that rare - a few percent of normal females have it - and is not usually clinically significant. However, your daughter could well have one or more defective genes on the normal, inactive X chromosome. If her father is normal, then the prediction would be that the X with the defective gene comes from the mother, who would be protected by her second X chromosome and random inactivation. If Dad carried the defective gene, he should have the same immunodeficiency. So an easy test would be to determine the parent of origin of the normal and deleted X chromosomes. This could be done by combined Chromosome Microarray and SNP analysis, offered by Baylor College of Medicine and other clinical genetic testing labs.

It is just becoming possible to look at all the genes on the X chromosome clinically. However, it is not yet routine, does not have perfect accuracy, and is expensive. If you want to pursue this I would recommend contacting a researcher interested in X-linked immunodeficiency, for example Jennifer Puck. She will probably want more documentation of the clinical nature of the immunodeficiency before embarking on laborious studies.

Sincerely,

Andrew R. Zinn, M.D., Ph.D.
Professor of Internal Medicine
University of Texas Southwestern Medical School


Q: 11: What is MEN - I understand it has something to do with chromosome 11.

The condition Multiple Endocrine Neoplasia (MEN) is known to be caused by a gene mutation on chromosome 11. There are literally thousands of genes on chromosome 11, and the gene that causes MEN is just one of them. Without more information, Im afraid this is all I can add.

Amy Curry
Certified Genetic Counselor


Q: 13;13 Robertsonian Translocation & repeated miscarriages?

The karyotype that you reported, 45,xx,t(13;13)(p11;q11), indicates that two copies of chromosome 13 are actually fused together. Thus, when the father contributes a sperm cell containing chromosome 13, the resulting baby will have 3 copies of chromosome 13, which causes Patau Syndrome. Most babies with this syndrome are not born alive, and those that are live-born have major medical problems present at birth, and typically die during infancy.
Thus, conceiving a child the usual way, by sexual intercourse, is not feasible, and I would advise any woman with a Robertsonian 13;13 translocation to use a method of birth control to prevent further pregnancies. However, a woman with this translocation could conceive a child by using a donor egg (an egg harvested from another woman, perhaps even a relative such as a sister), followed by in vitro fertilization (in which conception occurs in a "test-tube" and is implanted into your uterus). Your doctor will almost certainly be able to help you. This is the option that we would offer in the US.

Thomas Morgan MD
Medical Geneticist

Q: 13;14 Robertsonian Translocation.

Thank you for your inquiry to CDO. You asked how it is possible for a mother with a "Robertsonian" type of balanced chromosomal translocation involving chromosomes 13 and 14 [45,XX,der(13;14)(q10;q10)] to have a developing embryo despite trisomy 14 (extra copy of chromosome 14) or monosomy 14 (lacking one copy of chromosome 14).
In general, neither of these two chromosome abnormalities is compatible with life. Early miscarriage would be expected, except in the rare case of "trisomic correction" or "monosomic correction." This is admittedly a very complicated process to explain. However, it is a fact that some small percentage of a child's cells may have a trisomy or monosomy, whereas most do not, and that is explained by phenomena that go on at the cellular level to remove an extra chromosome from a cell, or make an extra copy of a missing chromosome.
I emphasize that this is very rare. It is not quite so rare to have a developing embryo with trisomy 13, however, because some embryos with trisomy 13 do not miscarry and can certainly be born alive.
I hope that this information is helpful to you.
Sincerely,
Thomas Morgan, MD

Q: 13p deletion - Would you provide us with information on a missing chromosome 13p. Our specialists can't provide us with any info.

The reason why you are having trouble finding information about a deletion of chromosome 13p is that, this chromosome change, by itself, would be unlikely to contribute to problems in a child. Certain chromosomes have very short "p" arms (the short ends of the chromosome as it is lined up in a picture) that consist of repetitive sequences of DNA. Chromosome 13 is one of these kinds of chromosomes. That is why someone can have a rearrangement of, say, chromosomes 13 and 14 in which the short arms of both the 13 and the 14 have been "lost" and the long arms of both chromosomes fuse and make a single large chromosome. This kind of chromosome rearrangement is called a 13;14 Robertsonian translocation. It is our current belief that individuals with a balanced form of this translocation, in the absence of other abnormalities, do not tend to have medical problems but do have an increased chance of having children who inherit an unbalanced chromosome combination.

There are other studies that the laboratory that studied your child's chromosomes can do that may help to clarify these results. Perhaps these have already been done. One is to study both parents' chromosomes. It may be that this unusual looking chromosome 13 is present in one of you and, therefore, is unlikely to be the cause of any problems in your child if both of you are healthy.

Another approach is to use a technique called FISH (fluorescence in situ
hybridization) in which a specific region of the DNA is examined by the use of "DNA probes". This allows specific areas of the chromosome to be studied in greater detail. There are DNA probes available for all of the ends of the chromosomes (telomeres). This is referred to as a telomere analysis.

When a cytogenetic laboratory performs a chromosome study they typically issue a karyotype report. On that report, there should be some interpretation of what the lab director actually saw when the study was done. A certified medical geneticist/genetic counselor can help families understand this kind of information and give you their impression about whether or not the chromosome change is causing a problem or if it is just a variation in chromosome structure.


Related Note:

It is, of course, impossible to interpret this kind of information without knowing the actual karyotype (e.g. 46,XX, etc.) and what other studies may or may not have been done. In my mind, the best solution is for the parents to get a copy of the karyotype report and consult with someone trained to explain it in person.

Myra Roche, Certified Genetic Counselor


Q: 15q delletion and ectodermal dysplasia

In the literature there are reports of about ~225 persons with deletion 15q13.3 [including 9 who had deletions on both chromosomes 15]. Not a single one of these patients also had ectodermal dysplasia. To the best of my knowledge, this area does not contain genes responsible for ectodermal dysplasia. Most likely, both these conditions are unrelated.

Iosif Lurie, M.D.
Medical Geneticist
CDO Medical Advisor


Q: 18: Please explain Triple Screen Test & Trisomy 18.

The triple screen is a screening test done during pregnancy that measures three different substances in a pregnant woman's blood, including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3). These substances are made either by a developing baby or the placenta and circulate in a woman's blood during pregnancy. The amount of these substances changes throughout pregnancy, and therefore, accurate dating of a pregnancy is very important for reliable interpretation of the test results. 

The triple screen is a screening test for two chromosome problems (Down syndrome and trisomy 18) and open birth defects. Approximately 60% of cases of Down syndrome and trisomy 18 can be detected by a triple screen. In addition, the AFP value alone is used to screen for open birth defects, such as spina bifida. Approximately 85% of babies with spina bifida can be identified in this way. Since the triple screen is a screen and not a diagnostic test, a result indicating an increased risk for a chromosome problem or open birth defect does not mean that a problem exists, but rather that the pregnancy is placed into a higher risk group. It is also important to remember that a result indicating no increased risk does not mean with certainty that a baby is unaffected with one of these conditions. Consequently, further diagnostic testing such as amniocentesis is offered following a triple screen result that indicates an increased risk for one of these conditions. 

Specifically for your situation, it sounds like there may be an increased risk for trisomy 18. Trisomy 18 is an event that occurs by chance and there is nothing done to cause it or anything that can be done to prevent it. Typically, ultrasound abnormalties would be present, however, ultrasound is only a screening test like the triple screen is, and cannot be considered diagnostic. The amniocentesis, however, will give a definite yes or no answer as to whether the baby has trisomy 18 or any other numerical or structural chromosome abnormality. 

Amy Curry CDO Medical Advisor 
Certified Genetic Counselor 


Q: 18: What about a chromosome 18 problem - preliminary prenatal tests indicate trisomy 18.

It sounds like your friend had a blood test called AFP-3 (triple screen) or AFP-4 (quadruple screen). Some doctors use the triple, some use the quad; they are essentially the same test with about the same degree of accuracy. This blood test is a screening test. That means that it DOES NOT diagnose anything; rather, it gives a risk estimate. This blood test will give a risk figure for basically 3 kinds of birth defects: open spine defects, Down Syndrome and a rare chromosome disorder called Trisomy 18. The test is only accurate if the laboratory has the correct information regarding the due date. For instance, if your friend was more than 2 or 3 weeks off in her due date, then the test would be inaccurately read. However, if the test is analyzed correctly, it will provide an estimate of the likelihood that the baby would have one of these conditions. It sounds like her test came back with an increased risk for Trisomy 18. Trisomy 18 means that there are three number 18 chromosomes instead of just two. All our chromosomes come in pairs and are numbered. There are 23 pairs of chromosomes or 46 chromosomes total. If a baby had three of #18, there would be a total of 47. However, Trisomy 18 is quite rare. Most fetuses will have visible abnormalities that can be seen with a good ultrasound. If the ultrasound is normal, then most likely the baby does not have Trisomy 18. In general, the chance that the baby would actually have Trisomy 18 when the blood test is abnormal is about 1 chance in 100, or 1%. The chance for a normal baby would then be 99%. I would have to look at her actual test result to be more specific, but that is what it sounds like from your description. Amniocentesis is the only way to actually count the chromosomes and be sure. The doctor advised her appropriately. She should be reassured that the risk is fairly low of a real problem, especially since the scan looked normal. All of this information should have been completely explained in the genetic counseling before the amniocentesis. There are also numerous pamphlets and brochures about all of this. You can look at one from a lab I often use at the following website: http://www.genzymegenetics.com/clinicalinfo/afp3.htm 

I hope this provides your friend with some reassurance. I am certain this has been very distressing, but in most cases everything is fine. 

Donna Wallerstein 
Certified Genetic Counselor 
CDO Medical Advisor


Q: 18q deletion and aggression.

Thank you for your inquiry regarding your son, who has been diagnosed
with an 18q deletion and suffers from emotional immaturity and self- aggression. Both of these issues are common in children and adults with 18q
deletions, and physicians from around the world have noted the same
psychiatric issues in their patients with this disorder. However, the precise
explanation remains unknown. The only treatments involve various combinations
of medications (often a difficult process of "trial and error" as I suspect
you already know), or hospitalization when necessary.

Sincerely,
Thomas Morgan MD
Medical Geneticist

Q: 1p36 deletion + Cantu Syndrome

Cantu syndrome is a very rare condition that involves, among other problems, growth and developmental delay and overgrowth of hair. It is presumed to be caused by an abnormality in a gene, but I do not believe the gene has been identified.

I found one report about a boy thought to have Cantu syndrome who was found to have a deletion at 1p36. I don't think this means that the two conditions are one and the same. Other patients with Cantu syndrome do not have the deletion. It may be a case of mis-diagnosis, or perhaps some cases of Cantu syndrome are caused by the deletion, and some are not. It is not clear at this time.

There is a good summary of 1p36 deletion (although it is quite technical) at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607872

Karen Heller
Certified Genetic Counselor
CDO Medical Advisor


Q: 1p36 deletion research

Patients/families are encouraged to contact Dr. Lisa Shaffer's Laboratory Manager, Caron, at glotzbach@wsu.edu


Q: 1q: In a 1q deletion - what does the future hold for my child?

We always begin discussions of such questions with a review of the
notion that evry child with chromosomal deltion syndrome is unique. The
breakpoints are different and there is great variability. We can never
draw iron clad conclusions from the literature.

Having said that, there are some commonalities that are reported. Many
individuals have a small head circumference. There often is a small
chin called micrognathia. Some have had cleft of the palate. Some have
had heart defects. Developmental disabilities are common in children
with this chromosomal variation. Low muscle tone (hypotonia) is also
seen. Within this is a great spectrum. Overall functioning and outcome
is difficult to predict. Only through ongoing developmental assessment
can anyone try to make predictions about the future. Clearly, careful
medical evaluation and developmental services are appropriate for your
child's care.

Dr. Robert Wallerstein
Medical Geneticist


Q: 1q21.3: Would you please explain an Abnormal Relative-Quantitative PCR (rqPCR) copy number result and how it relates to chromosome 1q21.3 duplication? And is this related to my son’s epilepsy and developmental delay?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

PCR - polymerase chain reaction – is a method allowing the multiplication of a tested area of DNA.  Relative quantitative means that the results of the tested sample are compared with a standard (usually a healthy person). This method is primarily used in cancer cytogenetics when an investigator wants to determine the percentage of leukemic cells in a patient's blood or to see how production of the tested gene has changed in the process of treatment. In constitutional cytogenetics it may be used to confirm results of microarray.

 

From a clinical point of view, I would like to know the position of breakpoints of this duplication. In the literature, there are articles describing two families where dup 1q21.3 was associated with epilepsy, but in the first family (Muhle et al.) the duplication was from 152.646 to 152.838 MBA, and in another Saudi family (Nasser et al.) from 150.814 till 150.873.  There are also three sporadic cases of dup 1q21.3 associated with multiple malformations (no other details) - 1, tetralogy of Fallot - 1 andosterior ureteral valves - 1. I do not know why this patient was tested, but if the duplication overlaps with duplication in Muhle family or in Nasser family it may be considered as a risk factor for epilepsy.

 

 


Q: 2 children born with chromosome disorders - first was said to be de novo - why did this happen?

The possibilities include an error in the parents' studies, a cryptic translocation not able to be determined, or gonadal mosaicism where one parent carries a cell line with the deletion in the gonads only.

Robert Wallerstein CDO Medical Advisor
Medical Geneticist


Q: 21: Explain risks of having a second child with Downs Syndrome.

If a parent has one child affected by Downs Syndrome - is there an increased risk of having a second child affected by this same disorder?

 

Answered by: Donna F. Wallerstein, MS
Certified Genetic Counselor

Straightforward Down Syndrome (Trisomy 21), in which there are three #21 chromosomes that are separate and distinct from each other, is not inherited.  It is an accident of nature and recurrence risk is generally quoted as 1% plus the mothers age-related risk.  For example, a 35 year old mother who already had a child with Down Syndrome would have a 1% plus 1 in 400 or 1.25% recurrence risk.  Families who have had one child with a chromosome abnormality are offered prenatal diagnosis (such as amniocentesis) in subsequent pregnancies because of this recurrence risk.

Some families have a translocation in which one #21 chromosome is attached to another chromosome.  In this situation, a parent with a balanced translocation (no genetic material missing or extra) is at increased risk to have a child with Down Syndrome.  Recurrence risk would depend on the exact translocation and whether it was the mother or father who was the carrier. 

There have been exceedingly rare reports of families who have recurrence of straightforward trisomies, although it is not usually the same one.  I personally have had several patients who have miscarried more that one trisomic fetus, but not the same chromosome was involved in each case.  It is theorized that some individuals are at increased risk for recurrent trisomy due to some mechanical error in cell division when the egg or sperm are formed.  This has not been proven or well studied.


Q: 21: Explain risks of having a second child with Downs Syndrome.

If a parent has one child affected by Downs Syndrome - is there an increased risk of having a second child affected by this same disorder?

Answered by: Donna F. Wallerstein, MS
Certified Genetic Counselor

Straightforward Down Syndrome (Trisomy 21), in which there are three #21 chromosomes that are separate and distinct from each other, is not inherited.  It is an accident of nature and recurrence risk is generally quoted as 1% plus the mother's age-related risk.  For example, a 35 year old mother who already had a child with Down Syndrome would have a 1% plus 1 in 400 or 1.25% recurrence risk.  Families who have had one child with a chromosome abnormality are offered prenatal diagnosis (such as amniocentesis) in subsequent pregnancies because of this recurrence risk.

Some families have a translocation in which one #21 chromosome is attached to another chromosome.  In this situation, a parent with a balanced translocation (no genetic material missing or extra) is at increased risk to have a child with Down Syndrome.  Recurrence risk would depend on the exact translocation and whether it was the mother or father who was the carrier. 

There have been exceedingly rare reports of families who have recurrence of straightforward trisomies, although it is not usually the same one.  I personally have had several patients who have miscarried more that one trisomic fetus, but not the same chromosome was involved in each case.  It is theorized that some individuals are at increased risk for recurrent trisomy due to some mechanical error in cell division when the egg or sperm are formed.  This has not been proven or well studied.


Q: 22q11.2: What are the differences between Velocardiofacial syndrome, DiGeorge Syndrome & distal 22q11.2 Syndrome?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

Velocardiofacial syndrome and DiGeorge syndrome are synonyms. DiGeorge Syndrome is typically used when a patient has a heart defect and immunological problems, but it is arbitrary.  There is a more rare "distal" 22q11.2 deletion, when patients have deletions in the area between 22 and 23.5 Mb.


Q: 2p deletion & intolerance or inability to digest fats or other foods?

Individuals with 2p deletions typically have signififcant delays as you describe. there are some characteristic physical features and decreased visual acuity. Nearly all have poor weight gain.
The issue of poor weight gain is one that is common to many chromosomal variations. The reasons for this are not clear. As you suggest, it could be due to poor use of nutrients, but is not clearly known. Growth is a very complex process that we all take for granted. It involves the proper absorption and utilization of many nutrients and bitamins as well as programmed cell growth. When there is a chromosomal deletion or duplication, this process is disturbed and there is decreased growth. In most cases, this can not be pinpointed as to the exact reason.

Robert Wallerstein, MD
Medical Geneticist

Q: 2q duplication & deletion developmental attainments

It is hard to predict what medical challenges may be in the future for children with chromosome changes. Every child grows and develops differently whether they have a chromosome change or not. We know that children with chromosome changes will most likely be delayed in their milestones and need special medical attention. In addition, it is difficult to know how your child will progress as her chromosome change has not been seen in other many other children. It is important to follow the development of your child closely and let her show us what she can and cannot do. When there is not much information in the medical literature, we need to take a systems approach and evaluate a child system by system to assess their status and then move forward. As we have said before, each child with a chromosome variation is unique on a molecular level and also clinically so it is very important to individualize.
Robert Wallerstein MD
Medical Geneticist


Q: 2q21qter and 12q15qter: My husband has been diagnosed with a balanced translocation - t(2;12)(q21.1;q15). What are our chances of carrying an unbalanced baby past 12 weeks?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

 

The most likely forms of unbalance, caused by t(2;12)(q21.1;q15) are der(2)t(2;12)(q21.1;q15) [deletion of the segment 2q21.1qter (~112 Mb) and excess for the segment 12q15qter (~60 Mb)] or der(12)(t(2;12)(q21.1;q15) [deletion for 12q15qter + excess for the segment 2q21.1qter]. In both cases the unbalance is too big to be compatible with life and any embryos with these types of unbalances will die in utero.

 

Even if we assume a segregation of 3:1 we can expect excess 12pter-q15 (~72 Mb) with excess 2q21.1qter (~112 Mb) or excess 2pter-q21.1 (~130 Mb) with excess 12q15qter. These variants are also 100% lethal.

 

A segregation of 1:3 will produce even more severe damage.

 

Therefore, all the possible variants of unbalance due to this translocation are incompatible with life, and if a pregnancy progresses until 12 weeks it means that the fetus has either a normal karyotype or is a balanced carrier.


Q: 2-vessel cord.

Most babies are born with a 3-vessel cord (2
arteries, 1 vein). Although a 2-vessel cord is reported more frequently in
babies who have medical problems at birth, most babies with a 2-vessel cord have no such problems. 2-vessel cords don't point directly to a particular specific problem, but other organs should be checked including the heart (by echocardiogram). Your daughter needs a formal consultation with a physician specializing in clinical genetics, to investigate why she has the health issues that she does. I certainly wish both of you the best. Sincerely, Thomas Morgan, MD Dept. of Genetics and Yale Child Study Center


Q: 2-vessel umbilical cord, missing right kidney, and thickened heart valve.

By ultrasound, the fetus has been found to have a 2-vessel umbilical cord, missing right kidney, and thickened heart valve. Most babies are born with a 3-vessel cord (2 arteries, 1 vein). Although many babies with an isolated 2-vessel cord do not have any other medical/developmental issues, some have heart, kidney, or other organ involvement. The precise developmental mechanism by which these organ systems are connected is not well-understood. Usually, it is not due to a well-defined genetic syndrome. However, a formal consultation with a physician specializing in clinical genetics should be done, as soon as possible, if it has not already been done. The geneticist may recommend that the baby have a chromosome study (karyotype), and perhaps also a chromosomal microarray study (looking for small deletions of chromosomes), probably shortly after birth. In addition, I would recommend that all the doctors who will be caring for the baby at birth be notified, in advance, that there are issues with heart and kidney function to be checked promptly at birth. I know you must be worried. However, many babies born with one kidney never run into serious problems (I saw a Yale student with one kidney in my clinic two weeks ago). The heart valve problem may or may not require treatment it is too soon to tell. Also, you rightfully must want reassurance that everything else is OK with the baby. Your doctors will do the appropriate studies to try to rule out other issues, but the reality is that all parents (and
grandparents) must wait to see, as the baby is born and grows up, that everything is OK. I certainly wish your whole family the best. Sincerely, Thomas Morgan, MD Dept. of Genetics and Yale Child Study Center

Q: 4(q32.3-q34.3) and deletion 4q34.3-qter & behavioral issues?

As I understand, your main inquiry was about a possible link between the behavioral issues and a diagnosis of inversion-duplication 4(q32.3-q34.3) and deletion 4q34.3-qter. Yes, there is a link, and especially with the deletion in this region. However, this does not mean that there is destined to always behave in this way. The frequency of the problem behaviors will vary with the environmental stimuli.
It is a challenge to identify the stimuli that make the behaviors worse, but if you can do it, then the clear objective would be to reduce or eliminate exposure to the particular stimulus that triggers the behavior. For example, it might be that a change in the usual routine is hard to take. If so, then not just parents, but all caregivers should understand that sticking to the routine is important. Another source of behavioral outbursts is inability to communicate wants effectively. Some children with language delay benefit greatly from learning some sign language for basic wants, or pointing to pictures of key wants.
I hope this information is helpful to you. We do not yet know the specific molecular explanation for this type of behavior in 4q34 deletion, but this should not prevent us from dealing with it effectively. I wish you the best. Sincerely, Thomas Morgan, MD Dept. of Genetics/Yale Child Study Center


Q: 45 XY der(13;13) Robertsonian Translocation - questions about infertility, affected offspring and inheritance of this translocation

1. The male who has a balanced Robertsonian translocation 45,XY,der(13;13)(q10;q10) may form only 2 types of sperm cells: sperm cells with two chromosomes 13 and sperm cells without chromosome 13. If the normal egg-cell will be fertilized by a sperm with 2 chromosome 13 it will cause trisomy 13 in an embryo (which may result in a miscarriage or in a baby with Patau syndrome). If the normal egg-cell will be fertilized by a sperm without chromosome 13 an embryo will have monosomy 13 (this pregnancy will result in embryonic death at very early stages, most likely even before pregnancy will be recognized). Therefore theoretically male with such translocation has no ways being a father of a normal baby. I do not think that a traditional assisted reproduction can help. Assisted reproduction for males having translocations allows to select normal sperm cells for fertilization. But if the person does not have normal sperm cells, there is no opportunity to do it.

The homologous t(13;13) are very rare. In my practice I had only one family who came to us after a birth of a child with Patau's syndrome. After diagnosing t(13;13) we told them about 100% risk. They did not trust us, continued to try and eventually had two more babies with Patau's syndrome.

Theoretically, there is one way of "rescue". If a sperm with 2 chromosomes 13 will fertilize an egg-cell without chromosome 13 (or if a sperm without chromosome 13 will fertilize an egg-cell with 2 chromosomes 13) the chromosomal complement of the fetus will be normal. I doubt, however, that it can be done artificially. Try to contact Reproductive Genetics Institute in Chicago: sometimes these guys are successful in previously unimaginable situations. Most likely their answer will be negative, but who knows...

2. The homologous Robertsonian translocations cannot be inherited. Your siblings cannot carry this translocation.

3. The general health prognosis for the carrier of t(13;13) is the same as for any other person: there is no specific risk associated with this condition.

Iosif Lurie, M.D., Ph.D.
CDO genetic consultant


Q: 45X/46X del (Y) inquiry.

45X/46Xdel(Y)(pter>q11.2) means that a person has a missing Y chromosome in some cells, and in the others, there is an X and Y chromosome, but the Y is abnormal, with a part of it deleted.  The Y chromosome specifies male sex, as you know, and depending on the mixture of 45X/46XY cells, individuals can be either male or female.  Males with this chromosomal diagnosis have a high risk of infertility, and can have abnormal testicular tissue with possible risk of a tumor called a gonadoblastoma.  If such abnormal tissue is detected or suspected, it must be removed surgically.  It is not possible to make predictions about cognitive development from the chromosome report.  The boy whom you are considering adopting should have an evaluation by a geneticist, a pediatric endocrinologist, and a physician specializing in international adoption.  Only with this information can you make a decision about what type of care this child will require.  I certainly wish you and the child all the best. Sincerely, Thomas Morgan, MD Washington University School of Medicine St. Louis Children's Hospital
 

Q: 45X/46XY mosaic questions...

Questions - The risks of future ambiguous genitalia.
- In case of testes tumour (Chirurgic to remove testes) – Will be normal his sexual activity?

Answers to above:
1. The risks of ambiguous genitalia do not change after birth. The

Q: 46 XX Male Syndrome SRY Positive

The literature emphasizes mostly fertility issues. Symptoms include small testes, gynecomastia (breast enlargement) and sterility, similar to 47,XXY Klinefelter syndrome, but without the tall stature usually seen in that condition. As with all chromosomal conditions, the phenotype varies. Sometimes there is ambiguous genitalia or mild penis abnormalities, and high resolution ultrasound is helpful. Andrew Zinn MD Medical Geneticist


Q: 46 XY dup(8) (q24.1 q24.3): Do you think there is a chance of an abnormal birth with an embryo with the following chromosomal results - 46 XY dup(8) (q24.1 q24.3)?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

The formula dup(8)(q24.1q24.3) shows that (most likely) it was a "standard" cytogenetic examination. We do not know the exact breakpoints and the size of the duplicated segment, but it is obvious that at least 20-25 Mb of DNA are duplicated.

 

Isolated duplications of 8q24 are very rare. After removing all cases with associated imbalances, all cases with mosaicism and all cases with small (less than 2 Mb) duplications I could find only a dozen reports which may be relevant to the issue (the list is below).

 

There is no syndrome associated with duplications 8q24.1q24.3, but all patients with large duplications in this area had multiple defects, including ACC (agenesis of the corpus callosum), ASD (atrial septal defect), DH (diaphragmatic hernia), CLP (cleft lip and palate), CP (cleft palate) and many others. All children showed a delay in psychomotor development. Most of these cases were reported not in special articles, but in abstracts of different meetings or were mentioned in the large group of abnormal results upon examination of some special group of patients. 

 

In any case it is necessary to perform a cytogenetic examination of both parents to exclude a balanced translocation or inversion in one of them.

 

Isolated Duplications:

 

Publication

Duplication

Conditions

Min & al., 2012  8q24 [6.0 Mb] none listed
Malvestiti & al., 2014  8q24.11q24.3 [25 Mb; 119.142-144.826] Hydrocephaly; Short stature; Dysmorphism; MR
Hordijk & al., 1998 8q24.11qter  Hearing defect; Webbed neck; Scoliosis
Farcas & al., 2016  8q24.12q24.3 [> 26 Mb] CP; Choanal atresia; Imperforate anus; Agenesis of the uterus; ACC; Dysmorphism
Ozdemir & al., 2012 8q24.12qter CLP; ASD; Dysmorphism; MR
Costa & al., 2009 8q24.2q24.3 Hypoplastic rostrum of the corpus callosum; Seizures; Hyperactivity; Dysmorphism; MR
Gijsbers & al., 2009 2011 8q24.2qter [12.87 Mb]  Behavioral problems
Reddy & al., 2012 8q24.23. [2.204 Mb; 137.043-139.248] Doubling of the right ureter and right kidney [stillborn]
Choucair & al., 2015 8q24.23q24.3 [9.726 Mb; 136.544-146.271] DH; MR
Bonaglia & al., 2004; 2005 8q24.3. [2.3 Mb] Epilepsy; Prominent metopic suture; Café-au-lait spot; Camptodactyly

Q: 47 XXY karyotype - female with premature ovarian failure.

Patient has no any abnormal physical signs, no mental retardation.

Additional testing recommended:


1. Examine chromosomes of gonadal tissue by karyotype if cells can be
cultured or by FISH on fixed tissues with X and Y centromere probes.
Perhaps there is mosaicism and the gonads are 46,XX or 45,X.

2. Examine the SRY gene. See this case report:
Brown, S.; Yu, C. C.; Lanzano, P.; Heller, D.; Thomas, L.; Warburton,
D.; Kitajewski, J.; Stadtmauer, L. :
A de novo mutation (gln2stop) at the 5-prime end of the SRY gene
leads to sex reversal with partial ovarian function. Am. J. Hum.
Genet. 62: 189-192, 1998. In this case, a second rare event is
required to explain the 47,XXY karyotype.

Andrew Zinn MD
Medical Geneticist
CDO Medical Advisor


Q: 47 XYY.

There is a lot of misinformation about XYY, stemming from a report in the 1960's that we now know to be false claiming that the extra Y chromosome is associated with increased criminal behavior (there is an unfortunate tendency for dramatic claims to get great media attention, with subsequent studies showing these claims are wrong getting hardly any press).

I do not know of any support group in the United States specifically for XYY. There is a very good web site about XYY in English from a support group in the Netherlands:

http://www.aaa.dk/TURNER/ENGELSK/XYY.HTM

I reviewed the information and consider it accurate.

Sincerely,

Andrew Zinn
Medical Geneticist

Q: 4p deletion - arching of the back?

The term for arching of the back is "opisthotonus," and it is a symptom rather than a specific clinical diagnosis.
It can be observed in many different disorders affecting the brain and control of muscle tone. Normally, our muscles contract when we tell them to, and pretty much remain relaxed at other times. There are some exceptions, such as when we first nod off to sleep and the whole body jerks a bit (sometimes startling a person awake again). If you open a sleeping person's eyelids, the eyes will typically be tilted all the way upwards, so it may be that you're catching your daughter in a half-asleep state. These movements of her eyes and arching of her back could all be due to general neuromuscular control issues that come up at times of sleep or certain stresses. However, I certainly agree with your pediatrician that an EEG is warranted. I hope that it will provide reassurance that these episodes are not seizures. Sincerely, Thomas Morgan, MD Dept. of Genetics Yale University

Q: 5;15 apparently balanced translocation - prenatal diagnosis?

How can we be certain that the translocation is balanced?
It is not possible, at this juncture, to be sure that the translocation is balanced. However, approximately 95% of apparently balanced translocations have no discernable effect on child development. About 5% of children have developmental delay, with or without distinctive physical features. Clearly, this is what parents are concerned about, but it is frustrating for the geneticist because there is no way to refine this probability estimate. Even if the breakpoints of the translocation were mapped precisely, this would have little or no predictive value. Frank disruption of a gene by a translocation may have no impact on the child; conversely, nondisruption of any gene may result in an adverse outcome (due to "positional effects" on gene regulation).
Therefore, there is no substitute for the passage of time, with careful examination of the child at birth, and close monitoring of developmental progress. This is of course true for any child, whether or not he or she has a balanced translocation - it is impossible to predict, a priori, a child's developmental outcome.
> 2. Would a CGH test improve this? Not likely. Only if a fairly large deletion exists (which is typically evident on a karyotype) will CGH add any information. I do not recommend CGH, because it is better to map each specific breakpoint precisely by using individual DNA probes (BACs), if the child has any developmental issues or has congenital anomalies not seen on ultrasound.
> 3. Do you have any specific information about this particular
> translocation?
The karyotype unfortunately provides information about the identity of the translocation that is too imprecise to make any comparisons with other children with what superficially resembles the same translocation. We treat each child's translocation as potentially unique until it has been fine-mapped using DNA probes. There is no reason to fine-map translocation breakpoints unless there is some possibly related developmental or medical issue in the child. Also, this procedure is time-consuming and not available as a clinical service. It is only done (for no charge) by researchers such as myself when a child's particular case demands it.
> 4. Could an unbalanced translocation have a normal ultrasound?
Yes. The normal ultrasound is quite reassuring, but it is not sensitive enough to detect subtle abnormalities.

My own personal view on how expectant parents might wish to conceptualize the unborn child with a de novo apparently balanced translocation is that it really should not add any significant excess worry. It is a fact of life that 2-3% of all babies (regardless of a translocation) are born with medical/developmental issues that are present at birth. The balanced translocation simply changes this probability by a couple of percentage points. A normal outcome is still the overwhelmingly likely result.

The most important thing for parents to remember is that a child with a balanced translocation, when he or she is old enough to think about starting a family, must be referred for genetic counseling. The balanced translocation carrier has a substantial risk of having offspring with unbalanced deletion/duplication syndromes. Genetic counseling, amniocentesis or chorionic villus sampling, and even pre-implantation genetic diagnosis would be available options for the child who is reaching adulthood and wishes to have children.

Thomas Morgan MD
Medical Geneticist


Q: 5p- and speech development.

Speech is a particular challenge for most children with 5p deletion syndrome, and so Adam's case is not atypical. When the syndrome was originally described, children with the most severe challenges were more likely to be identified, leading doctors to tell many parents that speech would be quite unlikely. We now know that many children have milder speech/language challenges, with development of sentence structure being feasible for some. With respect to a particular child, such as Adam, only time will tell what his actual communication mode will be, whether spoken language, sign language, or other forms of nonverbal expression. It is important for parents to focus more on communication than on speech itself, taking advantage of sign language, picture identification to express wants, or any other way that the child makes himself understood.

Thomas Morgan MD
Medical Geneticist

Q: 7: I just had a second miscarriage. Testing revealed Trisomy 7. Should I seek genetic counseling?

Approximately 50% or more of miscarriages are due to chromosomal abnormalities, and the main chromosomal abnormality that causes miscarriages is trisomy. Trisomy 7 is common in first trimester miscarriages. This is something that just occurred randomly by chance; either the egg or sperm that made this pregnancy was made with an extra chromosome 7, and when conception occurred, there were three number 7 chromosomes instead of the normal two. There has only been one report of trisomy 7 in the literature, and this may not have even been a "true" result. (Sometimes trisomy 7 can arise in a cell culture when the cells are growing so that they can be
analyzed, and not really be present in all the cells of the fetus).

Once a couple has had two unexplained miscarriages, chromosomes on the parents can be drawn in order to see if one of them carries a balanced chromosome rearrangement that does not cause them any health problems, but can predispose them to having pregnancies with unbalanced chromosomes. Since we know the cause of your most recent miscarriage to be a trisomy, this would not be recommended unless you had another miscarriage.

Amy Curry Certified Genetic Counselor


Q: 7: I just had a second miscarriage. Testing revealed Trisomy 7. Should I seek genetic counseling?

Approximately 50% or more of miscarriages are due to chromosomal abnormalities, and the main chromosomal abnormality that causes miscarriages is trisomy. Trisomy 7 is common in first trimester miscarriages. This is something that just occurred randomly by chance; either the egg or sperm that made this pregnancy was made with an extra chromosome 7, and when conception occurred, there were three number 7 chromosomes instead of the normal two. There has only been one report of trisomy 7 in the literature, and this may not have even been a "true" result. (Sometimes trisomy 7 can arise in a cell culture when the cells are growing so that they can be
analyzed, and not really be present in all the cells of the fetus).

Once a couple has had two unexplained miscarriages, chromosomes on the parents can be drawn in order to see if one of them carries a balanced chromosome rearrangement that does not cause them any health problems, but can predispose them to having pregnancies with unbalanced chromosomes. Since we know the cause of your most recent miscarriage to be a trisomy, this would not be recommended unless you had another miscarriage.

Amy Curry Certified Genetic Counselor

 


Q: 7: Please explain "+7" as a result of fetal testing due to a miscarriage.

The "+7" refers to an extra chromosome number 7 in all of the cells of the fetus. Normally we have two copies of each of our chromosomes, and this means that the fetus had three copies of chromosome 7, which can also be called "trisomy 7". This is incompatible with life because it is too much genetic information, and this is why a miscarriage occurred. Unfortunately, of all recognized pregnancies, about 10-15% or more end in miscarriage, mostly in the first trimester. As you know, fetal tissue can be analyzed to see if there is a chromosome abnormality. Around 50% of these fetuses will have a chromosome abnormality; it is very common. Of all chromosomal abnormalities in miscarriages, trisomies (what happened in your pregnancy) are the most common. The vast majority of chromosomally abnormal miscarriages occur to chromosomally normal parents, and the chromosome abnormality happened as a sporadic event in the making of the sperm or egg.

Amy Curry, Certified Genetic Counselor
CDO Medical Advisor


Q: 9 inversion & echogenic bowel and choroid plexus cyst.

The typical chromosome 9 inversion "heteromorphism" that is considered a normal variant in humans is inv(9)(p11q12).  I'm not sure if that is the diagnosis for your patient.  However, if it is, then it is presumably not causing the echogenic bowel or choroid plexus cyst.  It will be helpful to have parental karyotypes to confirm that this is the typical inversion 9 heteromorphism.  Assuming that a parent and child both have the inv(9)(p11q12) karyotype, then this is considered benign, and thus the karyotyping does not inform the discussion about whether the parents wish to continue the pregnancy.  The discussion would have to be based on the ultrasound findings alone, if no genetic diagnosis is apparent.  I typically would also do a chromosomal microarray study prenatally in a case like this, sending the sample to Baylor Diagnostic Labs (Kleberg Cytogenetics Laboratory). 
Best Regards,
Thomas Morgan, MD
Washington University School of Medicine
St. Louis Children's Hospital

Q: 91 XXXX - missing chromosome 17.

After the egg is fertilized by a sperm, the fertilized egg has 46 chromosomes. The fertilized egg, or "zygote," then copies the whole set of 46 chromosomes, and gets ready to divide into two cells. If that first cell division doesn't happen correctly, then there will be 92 chromosomes present in the undivided zygote. This zygote can then go on to divide, ultimately resulting in miscarriage. Tetraploidy is one of the more common causes of miscarriage. When tetraploidy happens once, the couple is not considered to be at higher risk for it happening again. An alternative, but presumably rare, mechanism for tetraploidy is the fertilization of an egg by 3 sperm all at once. Miscarriages, as you may know, are common (about 25-33% of all pregnancies end in miscarriage), and can happen to any couple. In general, when a couple experiences 3 or more miscarriages, then they should be referred to a board-certified clinical geneticist (physician specializing in genetics) for counseling and chromosomal analysis.
By the way, when there is an abnormal number of chromosomes in a cell, it is not unusual for one or more to be "lost" (extruded from the cell). Thus, it is is not a surprising finding to have a missing chromosome 17.
Thomas Morgan MD
Medical Geneticist
Yale University Medical Center

Q: 9qh+ and miscarriage?

9qh+ is a heterochromatic variant. It’s kind of hard to define as an entity since there is a continuous range of very short to very long in the 9qh region. Some of these can, in fact, be huge, equaling or exceeding the length of the entire euchromatic part of the long arm. Overall, heterochromatin is not known to participate in the process of crossing over so it shouldn’t create any problems with meiosis. I’m unaware that it would have any effect at all on mitosis. I think the strongest argument to be made with the scenario presented is one of coincidence.

Dr. Andrew Zinn
Medical Geneticist




Q: 9qh+: What does 9qh+ mean?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

 

It means that the heterochromatic segments on the long arm of chromosome 9 are unusually long. It is a normal variant and does not have any significance. 25-30 years ago this variant was considered a reason (or a risk factor) for recurrent miscarriages.


Q: Abnormality, anomaly and psychomotor delay - what are the meanings?

"Abnormality" and "anomaly" mean essentially the same thing in the medical setting. There is a slight difference in that an "anomaly" can be appreciated by an observer even when the "range of normal" is undefined.

"Psychomotor delay" refers to delayed cognitive development as well as delayed acquisition of fine and gross motor skills such as picking up small objects, or walking, respectively.

>Thomas Morgan MD

Q: ABR, hearing loss in children with chromosome deletions.

I am not sure as to what the neurologist is referring. The ABR (auditory brainstem response) is a specialized form of hearing testing. The cause of the hearing loss should not affect the test. The chromosome issue that you son has should not affect the accuracy of the testing.

The following is a description of ABR testing from the Boston Children;s Hosptial website:

The ABR is one type of evoked potential or EEG hearing test. The ABR test uses computer-averaged changes in EEG activity, time-locked to the onset of repetitive sounds, to determine whether the particular intensity presented could be heard. The test must be performed during sleep, either natural or sedated, in a young child. Chloral hydrate sedation usually is given to children age 6 months and older, with most infants younger than 6 months tested in an unsedated sleep following a feeding. Three scalp electrodes are applied. Clicks and tonal signals are presented through an earphone and, if appropriate, through a bone conduction oscillator. A 3-frequency audiogram (1,000, 2,000, and 4,000 Hz) may be obtained by ABR for each ear, within 5-10 dB of actual thresholds, with some limitations on accuracy if there is a very steeply sloping high-frequency hearing loss. ABR thresholds for click stimuli, without frequency-specific tonal thresholds obtained, can serve as an effectiv! e scree ning but do not rule out a loss in a specific frequency range. The ABR waveform in response to high-intensity clicks can be used to measure neural conduction times in brainstem auditory pathways. An automated screening version of the ABR test can be used for newborn hearing screening prior to discharge from the hospital. For children age 0-6 months; prematurely born or developmentally delayed age 0-12 months; older infants or toddlers who had a regular (behavioral) audiological evaluation but hearing loss could not be ruled out.





Q: Absence seizures and abnormal EEGS?

Absence seizures also called petit mal seizures are brief generalized seizures manifested by a 10 to 30 second loss of consciousness with eye muscle flutterings at a rate of 3 per second with or without loss of muscle tone. A person can suddenly stop any activity and resume it after the event. This is usually a stop and stare kind of phenomenon.

Seizures happen because of a discharge of electrical activity that is out of the usual pattern of electrical flow thropugh the connections of the brain. If a person has a structurally different brain, he or she is at increased risk for variant patterns of electrical activity and therefore is at increased risk for seizures. Since people who have chromosomal variations often have structural variations in their brain, they are at increased risk for seizures. there is nothing inherant in the chromosomal variation that causes the seizures per se.

A complicating factor in this is that seizures can present very atypically. The clinical manifestations of a seizure can be very different from what is classically described. In children with chromosome variations who have atypical responses to other issues, the seizures can be atypical as well with behaviors that are not clearly seizures.

The EEG (electroencephalogram) is a way to look at the electrical pattern of the brain and can detect seizure activity and also variant patterns of electrical activity. The variant in electrical actoivity is not a seizure. It could develop into seizure activity in the future or never progress and just be a finding on the study. It can get very murky figuring the whole process out sometimes. A skilled neurologist is essential to good management. My bias is to do EEG testing on children with chromosomal variations who show any unusual or unexplained behavior.

Robert Wallerstein MD


Q: Acquired deletion of chromosome 4.

Thank you for contacting us about your daughter, who has a very high white blood cell count, with an acquired deletion of chromosome 4. I understand from your email that by the term "acquired," you mean that the deletion occurred presumably in the abnormal white blood cells only, and not in the rest of the cells of her body. If your daughter is otherwise normally developed, and healthy except for the white blood cell disorder, then we expect that only the white blood cells would show this abnormality. Although the loss of a chromosome from white blood cells is strange and alarming for a parent, your daughter does not have a chromosomal disorder such as the other children whose parents typically contact this website. It is not uncommon for abnormal white blood cells to acquire chromosome abnormalities, and it does not add much information that a parent would need to know beyond the understandable concern that you have for her successful treatment with a bone marrow transplant. I have much hope for her and wish her well. A focus on this treatment, and not on the chromosome 4 deletion, is best right now. If the treatment is successful, the white blood cells will be normal again. Sincerely, Thomas Morgan, MD Yale

Q: An amniocentesis and a micro-array had different results. Could the amniocentesis be incorrect?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

"Standard" cytogenetic examination (when chromosomes are analyzed under microscope) cannot detect all small rearrangements. That is why if a "standard" examination shows some unusual abnormal results, more precise molecular techniques should be applied.  If my understanding of your report is correct, it was found that your daughter-in-law has a translocation of part of chromosome 20 onto another chromosome and there is no loss or gain of chromosomal material.  However (if neither your son nor his wife are the carriers of a balanced translocation), the presence of two translocations (at least four breakpoints) in the fetus is highly unusual and a detailed ultrasound monitoring of the fetus is necessary.


Q: Anencephaly & Trisomy 18?

Your specific question is whether or not anencephaly is related to Trisomy 18. The answer is that it is impossible to be certain, but anencephaly is only very rarely seen in association with Trisomy 18 and may certainly be coincidental. In addition, there is no information in your email to suggest that the fetus with anencephaly had Trisomy 18 or any of its associated features (such as clenched hands with overlapping fingers, cardiac defects, etc). Given this scenario, the most likely explanation would be that the two conditions were unrelated, but it would not be possible to rule out entirely a very unusual recurrence of Trisomy 18, with the first case having anencephaly. But there is no basis on which to draw that conclusion.

It is true that supplementation with high doses of folic acid (to be determined by a physician) are recommended following a pregnancy with anencephaly or other neural tube closure defects, and should commence well before a subsequent pregnancy.

Thomas Morgan
Medical Advisor
Medical Geneticist


Q: Are there progressive chromosome disorders? My daughter has a deletion and has gone from average to having significant delays.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

I am sorry to learn of your daughter’s increasing medical problems.  
 
Generally deletions (and any other chromosomal disorders) are non-progressive conditions.  A deletion of a gene, involved in a complex 1 of the respiratory chain, itself does not have to be harmful, because these genes may manifest defects only in a homozygous condition. 
 
I see two possible explanations for this type of progression in your daughter: 
 
1) The deletion of one copy of the gene, involved in a complex 1 of the respiratory chain, is associated with a mutation of another copy of this gene on the intact chromosome. (There are several reports in the literature documenting the phenotype of an autosomal-recessive condition found in patients having a deletion of a significant chromosomal segment and a mutation of the same gene on another homologue (one of a pair of chromosomes)).
 

2) Your daughter may have another condition (e.g., mitochondrial disease) which is unrelated to her chromosome deletion. 


Q: Are there sophisticated genetic tests available as a result of the human genome project?

The answer is yes, sometimes. Let us explain. First, let’s start with a review of what testing is currently available.
Routine chromosome analysis also called karyotyping looks at the chromosomes in black and white and their form. There are black and white stripes that are called bands that are numbered so we can refer to various chromosomal regions without seeing the chromosomes directly. In a standard chromosome analysis, there are 250 to 450 bands. As chromosomes are stretched, the bands split into sub-bands. High-resolution chromosome studies have 550 to 750 bands. This can help to identify chromosomal changes that may not be evident in the routine study.
FISH ( fluorescent in situ hydridization) is a technique where molecular probes for a particular region are used with a fluorescent tag to identify if a specific region is present or not with a color signal. This can be used to see deletions not identifiable on high-resolution studies. FISH has many uses. There are many different probes that can be used with the FISH technique to give good information.
FISH has lately been used in 2 technologies to help identify subtle chromosomal changes:
Subtelomeric probes and SKY. Subtelomeres are the regions on the chromosomes right near the tips. Subtelomeric probes are a set of 86 probes that looks at these regions to try to detect a very small deletion or translocation. It is thought that if there is a translocation, it will often involve the subtelomeric region and therefore we can track where these subtelomeres. Remember that there are 46 chromosomes so why aren’t there 92 subtelomeres? A good question- a few of the subtelomeric regions are so closely like each other that the probes do not distinguish them one from another. Some studies tell us that as many as 5 to10% of children with unexplained mental retardation will have a subtelomeric rearrangement not visible on other techniques.
SKY is a shortened term for spectral karyotyping. This is a technique where there are FISH probes for each chromosome (24 probes one for each pair 1 to 22 and one for X and one for Y). The technique is not so widely available as the subtelomeric probes, but can be used to look for complex rearrangements that do not just involve the tips of the chromosomes. It is sometimes used on cancer cells and is often a research technique. In my experience, it is used on a limited basis in patient care, but that may change in the future.
Now back to the original question: how has the human genome project helped with availability of genetic testing? As more information is known about where genes are located on the chromosomes and how these genes are characterized, there is much more testing available for these single genes are for chromosomal regions. We are able to look at a molecular level at certain genes and regions to get very important clinical information. For example, if a family has a chromosomal rearrangement that involves a region with some known genes in that region, we can look specifically for their involvement to help us know if the medical issues associated with that gene are of a concern for that family. This will get more commonly available as more is known to improve our ability to get knowledge about the health of the individual in question.

Robert Wallerstein M.D.
Medical Geneticist

Q: Are you born with 13q deletion? Can it happen later in life? Is there any information on the net that I can read about this? Thank you so much.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

In some types of leukemias, chromosomal abnormalities occur in abnormal blood cells. It is most likely that if other tissues (for example, skin cells) are tested, your karyotype will be normal.  CLL ( Chronic lymphocytic leukemia ) are not congenital (present from birth), but occur when cells are being transformed. Cytogenetic examination of people having CLL is used to determine the prognosis of disease and possible treatments. These abnormalities do not constitute chromosomal disorders. Your oncologist or hematologist will better explain the significance of the deletion that was found in your cells.

Best of luck to you. I hope this was helpful. 

 


Q: Audiologic neuropathy.

Hearing loss is associated with a variety of chromosomal variations. The medical literature
shows that auditory neuropathy has been seen in children with a wide
variety of other medical issues. It is not clear to me that a large number of
children with chromosomal variations have this form of hearing loss. Since
auditory neuropathy has altered brain waves as part of its definition, it would
seem likely that this could be associated with chromosomal variations.The
definition of auditory neuropathy is evolving. Below is a definition.

The following is a quote from a paper written by Drs. Rapin and Gravel at
Albert Einstein College of Medicine: The term "auditory neuropathy" is being
used in a rapidly increasing number of papers in the audiology/otolaryngology
literature for a variety of individuals (mostly children) who fulfill the following
criteria: (1) understanding of speech worse than predicted from the degree of
hearing loss on their behavioral audiograms; (2) recordable otoacoustic
emissions and/or cochlear microphonic; together with (3) absent or atypical
auditory brain stem responses.

Cochlear !
implant
ation, where a computer assisted device is planted in
the brain, has been used as a treatment. Knowledge in this area is evolving
about the best treatments.

Robert Wallerstein MD
Medical Geneticist
Donna Wallerstein
Certified Genetic Counselor



Q: Autism & behavioral treatment techniques?

Chromosomal deletions affect brain development by altering the normal developmental pathway. This means that the chromsomes code for certain proteins that are necessary at certain times in the formation of our brains. When these proteins are altered due to chromosome deletionor other genetic event, the functioning of the brain is different. Autism and autistic-like spectrum are such alterations. We do not understand the exact causes of these conditions. We do know that children with chromosome alterations are at high risk for these conditions. This goes back to some alteration on the normal developmental pathway.

Regardless of cause, children with an autistic-like disorder seem to benefit from educational startegies. The goal is to establish or stimulate connections within the brain to improve functioning. It is difficult to comment upon whether a specific therapy or modality will be helpful for a givewn child. This seems to be a fairly individual matter. Children with chromosomal alterations do benefit at about the same rate as other children with aitism or related disorders. Essentially at this point in medical time, we treat the symptoms. As more is understood in the future, perhaps a treatment that looks at the underlying reasons for the communication and behavior disturbance will be identified and we can treat an underlying problem. That is a long way off in the future. For now, I would concentrate on discussing with educators that various modalities available and trying to select one that is working for your child.

Dr. Robert Wallerstein, Medical Geneticist
Donna Wallerstein, Genetic Counselor


Q: Autism & Chromosome Abnormalities.

We evaluate a large number of autistic children in our practice. Autism is a description of a developmental disability related to problems with social interaction as one component. There are a large variety of chromosomal issues that have been associated with autism. All infrequently. The majority of children with autism have no known cause at present.
Donna Wallerstein
Certified Genetic Counselor

Q: Autism as genetic basis & interstitial deletion of chromosome 11q (q14.2q21.2)

Autism is a disturbance of social interaction that can be associated with learning disabilities. We usuually refer to this as autistic spectrum disorder because it is just as the name implies a wide spectrum with much variability. PDD refers to pervasive developmental disorder. This is a category that is essentially (to oversimplifly) mild autism.
Now, I believe that you are correct is saying that autism has a genetic basis. This basis is very diffuse and not well understood. In the medical literature, there are many different chromosome variations reported in children with autism. In my practice, we evaluate many children with autistic spectrum disorder and find some chromosomal variation. The issue is that the variation are not consistent. We find anomalies of different chromosomes and not in all children. We believe that there are other single genes involved that are not yet characterized.
So, having said that, autism is a description of a developmental profile. This has many causes. There are many genetic syndromes assocuated with a similar profile. There are many different diagnoses of the medical condition. Autistic spectrum disorder is a descriptiono f that profile. We use that as a diagnosis to decide what services will benefit a child educationally. It is a very mixed bag. A child with autistic spectrum disorder may or may not have another diagnosis explaining the cause for the developmental disturbance. They are not mutually exclusive.
I don't think that if a child had a genetic diagnosis that a diagnosis of autisnm is less likely to be made. It is just that the chromosomal diagnosis is more specific to the at child and implies developmental issues associated with it so a given practitioner may be more likely to use that diagnosis with the child in terms of services or categorization, but autism may still be present or not as the developmental profile of the patient.
Many children with developmental delay show autistic features. This refers as mentioned above to a disturbance in their social interaction. Learning and social interaction are closely linked so variation in one often affects the other. It is probably not possible to separate the two as to which is a primary and a secondary issue. I work closely with the Institute for Child Development at my hospital and we see many children with a variety of delays and autistic features. It is a wide spectrum of traits and variation that we do not yet fully understand on a medical or genetic basis. Hopefully, there is new information all the time, but a long way to go to understand these conditions.
Donna Wallerstein, Certified Genetic Counselor
Dr. Robert Wallerstein, Medical Geneticist


Q: Balanced Reciprocal Translocation: My wife has a balanced translocation. What are the chances of having a healthy child? We have lost 3 pregnancies.

The type of chromosome rearrangement that your wife has is called a balanced reciprocal translocation. Balanced reciprocal translocations are thought to occur at a rate of approximately 1 in 500 individuals in the general population. Balanced reciprocal translocations happen when breaks occur in two or more different chromosomes and the resulting chromosomal fragments swap places. No chromosomal material has been lost or gained and so the vast majority of carriers of a balanced reciprocal translocation do not have any symptoms. When a person who carries a balanced translocation has children, there is a possibility that the baby will not inherit the complete set of information. Carriers are at risk of producing offspring with part of one chromosome missing (only one copy instead of two) and part of the other chromosome extra (three copies instead of two). These translocations are called unbalanced translocations and may lead to miscarriage or the birth of children with symptoms including mental retardation and birth defects because this extra and missing chromosomal material may contain hundreds to thousands of genes important for the growth and development of a baby. It is possible that your previous miscarriages had an unbalanced
translocation.

It is important to realize that your wife's chromosomal material is all present; it is just arranged differently. Because there is no extra or missing chromosomal material, your wife should not have any health problems related to the rearrangement. When a person with a balanced translocation reproduces, there is a chance that he or she will make an egg or sperm that does not have the correct amount of genetic material. When the eggs or sperm of a person with a balanced translocation are made, the chromosome material does not necessarily divide evenly. Half of the eggs will be made with the correct amount of chromosome material (A and B below), while the other half will have an unbalanced amount (C and D below). The four possibilities for a mating between a person with a balanced translocation for example between 1 and 2 and a person with normal chromosomes are as follows:

A) Normal chromosomes
B) Balanced translocation carrier
C) Missing part of chromosome 1, extra part of chromosome 2
D) Extra part of chromosome 1, missing part of chromosome 2

Possibilities A and B above would result in an individual with the normal amount of chromosomal material, while possibilities C and D would not. For possibility C and D, because there is an abnormal amount of chromosomal material, the fetus would not develop normally and the pregnancy will often end in miscarriage. If the pregnancy did not end in miscarriage, the baby would most likely be born with physical birth defects and mental retardation.

Theoretically, it would be expected that the four possibilities listed above would occur in equal proportions, meaning that a baby with an unbalanced amount of chromosomal material would be conceived 50% of the time. However, the actual observed chance for an individual who is a balanced translocation carrier to have a baby with unbalanced chromosomal material is less than 50%. One possible reason for this is that many fetuses with unbalanced chromosomes will miscarry early in pregnancy. However, there is a good chance that you will conceive a pregnancy with the normal amount of chromosomal material.

Amy Curry
Certified Genetic Counselor


Q: Balanced translocation 3;4 repeated miscarriages.

Thank you for your inquiry to CDO. In general, a balanced chromosomal translocation such as a translocation of chromosomes 3 and 4 presents a theoretical chance of 25% that a child would inherit normal chromosomes 3 and 4, and a 25% chance that the child would inherit the parental balanced translocation. That adds up to 25% + 25% = 50% chance of having a child with normal or balanced chromosomes.
There remains a 50% chance of an unbalanced deletion/duplication syndrome, that may either result in miscarriage, or in the birth of a child with presumably major medical/developmental issues. There is no good statistical method to determine whether or not a pregnancy will end in miscarriage or live birth.
Accordingly, all individuals with a balanced translocation should receive comprehensive preconceptual counseling from a clinical geneticist (a physician specializing in human genetics). I certainly wish you the best in your efforts to conceive a child. Sincerely, Thomas Morgan, MD Yale Dept. of Genetics/Child Study Center

Q: Balanced translocation carrier - repeated miscarriages - What % of eggs should we expect to be affected by my translocation?

Given a balanced translocation, the theoretical probabilities are as follows for any randomly chosen egg:

50% unbalanced duplication/deletion

25% balanced chromosome rearrangement

25% normal chromosomes



It is important to remember that the above probabilities are theoretical only, and that individual results may vary by chance. In addition, the figures cited should not be considered as the probability of having a "healthy baby."

Besides the specific chromosome issue, fetal development depends on many other factors. I wish you the best in your efforts to conceive.



Sincerely,

Thomas Morgan, MD


Q: Balanced translocation carriers - both parents.

Your question was about the "odds for a healthy child," given that both parents are balanced reciprocal translocation carriers involving different chromosomes. First, I would reframe the question slightly, because no doctor can ever predict whether or not a child will be healthy. Children with perfectly normal chromosomes may or may not be healthy. However, a geneticist can provide the theoretical probabilities that a specific chromosome abnormality would, or would not, be inherited by the child, with each pregnancy:

1. probability of normal chromosomes 7,9,11,20: 1/16
2. probability of double balanced translocation: 1/16
3. probability of maternal balanced 7;11, normal paternal 9 and 20: 1/16 4. probability of paternal balanced 9;20, normal maternal 7 and 11: 1/16

Probability of any of the above: 1/4
Probability of NONE of the above: 3/4

If one assumes theoretically that none of the apparently balanced translocations would have any impact on fertility or development, then there is a 25% chance, with each pregnancy, of a child with balanced chromosomes. It is unclear to what extent liveborn offspring with abnormalities would be possible among the remaining 75% of theoretical conceptions with unbalanced chromosomes; most would likely result in miscarriage.

Thomas Morgan, MD
Dept. of Genetics/Yale Child Study Center
Yale University

Q: Balanced translocation involving the X chromosome & risk of anomalies?

The risk I usually cite of multiple congenital anomalies or developmental delay with a de novo balanced translocation is 5%. I don't know of any specific figures for translocations involving the X chromosome. While they are relatively rare, there are hundreds of cases in the medical literature, so you are not alone. Remember that the cases that are reported tend to be the ones that are the most severe. Certainly the normal ultrasound reduces the risk in your case. However, there is a significant risk (percentage again unknown, but I would guess at least 25%) that the girl will experience premature ovarian failure (essentially menopause), defined as cessation of menses before age 40. This may even occur before puberty. The ovaries are particularly sensitive to X chromosome abnormalities of any sort. Except for infertility, the symptoms of ovarian failure are easily treated with hormone replacement, and many women with this problem lead normal, happy lives.
Andrew Zinn Medical Geneticist

Q: Balanced Translocation: My wife has a balanced translocation. What are the chances of having a healthy child? We have lost 3 pregnancies.

The type of chromosome rearrangement that your wife has is called a balanced reciprocal translocation. Balanced reciprocal translocations are thought to occur at a rate of approximately 1 in 500 individuals in the general population. Balanced reciprocal translocations happen when breaks occur in two or more different chromosomes and the resulting chromosomal fragments swap places. No chromosomal material has been lost or gained and so the vast majority of carriers of a balanced reciprocal translocation do not have any symptoms. When a person who carries a balanced translocation has children, there is a possibility that the baby will not inherit the complete set of information. Carriers are at risk of producing offspring with part of one chromosome missing (only one copy instead of two) and part of the other chromosome extra (three copies instead of two). These translocations are called unbalanced translocations and may lead to miscarriage or the birth of children with symptoms including mental retardation and birth defects because this extra and missing chromosomal material may contain hundreds to thousands of genes important for the growth and development of a baby. It is possible that your previous miscarriages had an unbalanced
translocation.

It is important to realize that your wife's chromosomal material is all present; it is just arranged differently. Because there is no extra or missing chromosomal material, your wife should not have any health problems related to the rearrangement. When a person with a balanced translocation reproduces, there is a chance that he or she will make an egg or sperm that does not have the correct amount of genetic material. When the eggs or sperm of a person with a balanced translocation are made, the chromosome material does not necessarily divide evenly. Half of the eggs will be made with the correct amount of chromosome material (A and B below), while the other half will have an unbalanced amount (C and D below). The four possibilities for a mating between a person with a balanced translocation for example between 1 and 2 and a person with normal chromosomes are as follows:

A) Normal chromosomes
B) Balanced translocation carrier
C) Missing part of chromosome 1, extra part of chromosome 2
D) Extra part of chromosome 1, missing part of chromosome 2

Possibilities A and B above would result in an individual with the normal amount of chromosomal material, while possibilities C and D would not. For possibility C and D, because there is an abnormal amount of chromosomal material, the fetus would not develop normally and the pregnancy will often end in miscarriage. If the pregnancy did not end in miscarriage, the baby would most likely be born with physical birth defects and mental retardation.

Theoretically, it would be expected that the four possibilities listed above would occur in equal proportions, meaning that a baby with an unbalanced amount of chromosomal material would be conceived 50% of the time. However, the actual observed chance for an individual who is a balanced translocation carrier to have a baby with unbalanced chromosomal material is less than 50%. One possible reason for this is that many fetuses with unbalanced chromosomes will miscarry early in pregnancy. However, there is a good chance that you will conceive a pregnancy with the normal amount of chromosomal material.

Amy Curry
Certified Genetic Counselor

 


Q: Balanced translocations + IVF.

Carriers of balanced translocations have a risk for recurrent miscarriages. The theoretical risk of conception involving unbalanced chromosomal deletions or duplications is 50%. However, on average, the actual risk is 10-15% for having a liveborn child with an unbalanced set of chromosomes. We assume that miscarriages, recognized or unrecognized, account for the remainder.
The probability of a balanced translocation carrier having a child with normal chromosomes is 25%. In addition, there is a 25% chance of having a child with the same balanced translocation as the parent. That adds up to a 50% chance of conception involving no specific deletion/duplication syndrome related to the balanced translocation.
Preimplantation genetic diagnosis is a procedure in which a single cell is plucked from an early embryo, following IVF, and tested for a specific chromosomal diagnosis. Balanced translocation carriers undergoing IVF should discuss this procedure with the specialist who is performing IVF, or with a board-certified clinical geneticist.
I certainly wish you the best in your efforts to conceive. Sincerely, Thomas Morgan, MD Yale University Dept. of Genetics/Yale Child Study Center

Q: Behavioral issues in Turner Syndrome Mosaic.

There are numerous studies on behavioral abnormalities associated
with Turner syndrome. One study in 1994 found that girls with Turner
syndrome were more immature, hyperactive, and nervous, and had poorer
peer relations, greater difficulty at schooling, and more problems
concentrating than their peers. Mosaics tended to have milder
difficulties. A second 1994 study found that children with TS had
behavioral problems in the areas of impulsivity and medical
noncompliance. A third study in 1995 found that girls with Turner
syndrome were more immature than the XX girls, with weaker social
relationships, school performance, and self-esteem. A decline in self-
esteem was also documented for the girls with Turner syndrome as they
moved into early adolescence.

Nonverbal learning disabilities are also common in TS and may
contribute to these behavioral difficulties.

Andrew Zinn MD
Medical Advisor
Medical Geneticist

Q: Bipolar Disorder - Genetic Testing

In general, the risk of bipolar disorder developing in a first degree relative (child or sibling) of an individual with known bipolar disorder is about 5-10%; the relatively increased risk is due to the influence of highly complex genetic and environmental factors. All children or siblings of a person with bipolar disorder should be counseled by a psychiatrist or psychologist regarding the need to seek immediate psychiatric assistance if signs of bipolar disorder occur.
When an UNAFFECTED first degree relative of a person with bipolar disorder has a child, the risk that the child will develop bipolar disorder is probably not significantly higher than the lifetime risk of developing bipolar disorder for any randomly selected person in the general population, which is about 1% (1 in 100).
The definition of "unaffected first degree relative" deserves some thought. It presupposes that the person potentially at risk has been carefully evaluated by a physician or psychologist with expertise in diagnosing bipolar disorder, and that the at-risk person is old enough to have shown at least some evidence of bipolar disorder. Such physicians will be able to detect unusual cases of bipolar disorder which actually represent uncommon genetic syndromes (such as 22q11 deletion) that may be associated with a higher risk of some behaviors in the bipolar category.
There is no validated clinical genetic test for bipolar disorder at this time. At some point in the future, progress in this area is likely. However, due to the complexity of the genetic influences on risk of bipolar disorder, when neither member of a couple planning to have children has bipolar disorder or definite bipolar traits, the increase in risk of bipolar disorder in their current or future children, if any at all, is likely to be small. Thomas Morgan, MD Dept. of Genetics Yale University

Q: Bipolar illness: Is Manic Depression (Bi-Polar illness) hereditary?

Donna F. Wallerstein, MS, Certifed Genetic Counselor

Bipolar illness, also known as manic depression, does seem to have some genetic component. It is not strictly hereditary in the way that cystic fibrosis is inherited, passed from parent to child. It is more like diabetes, where you may see it clustering in a family, but in no particular pattern. Many families with one person with bipolar illness will have other family members who have only depression without the "mania" or ups. Psychiatric disorders or affective disorders are not caused by chromosome deletions or rearrangements, but are considered "multifactorial" in origin, many that both genetic and environmental factors interact to cause a person to have the condition.

 


Q: Blighted ovum, triploidy, how long to wait before becoming pregnant again?

If the triploid pregnancy turns out to be partially molar, then hcg levels should be monitored until they return to zero. I believe the standard recommendation following a molar pregnancy is a 6 month wait after hcg levels have returned to zero before attempting another pregnancy. If the pathology is normal, then a 3 month wait - 3 normal menstrual periods- is the standard waiting period. You may wish to consult a perinatologist about appropriate monitoring and time frame for attempting another pregnancy. Triploidy is rarely recurrent, but some couples will opt for prenatal diagnosis in a future pregnancy. A genetic counselor can review the various options for prenatal diagnosis in detail - 1st trimester screening, 2nd trimester screening, chorionic villus sampling, amniocentesis and the risks, benefits and limitations of each. Since the cause of miscarriage in the first pregnancy is not known, a genetic counselor may also recommend further screening to rule out any issues with thrombophilia or other treatable causes of loss.

Q: Calorie addition in children with chromosome disorders?

Adding calories is a challenge. A nutritionist or other health professional needs to assess each child individually. As you mention, some strategies are to add more sugar or more fats through oils. Also, there are balanced nutritional products with multiple nutrients. Clearly, there are down sides to any intervention. Increasing fats for example could lead to problems later. However, the benefits of increasing body mass are important for a child with poor weight gain. Most children's metabolism can satisfactorily handle any dietary change. So the bottom line is that the question is complex. There are no across the board answers. The goal for each child needs to considered and what the child will eat needs to be taken into consideration. In the best of all possible worlds, more balanced nutrition would be the goal.

Robert Wallerstein
Medical Geneticist

Donna Wallerstein
Certified Genetic Counselor

Q: Can a “vanishing twin” leak their genetic code to a surviving twin, making the surviving twin a mosaic containing both genetic codes, one that is their own and one that is from twin sibling?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

Editor’s note: Vanishing twin syndrome was first recognized in 1945. This occurs when a twin or multiple disappears in the uterus during pregnancy as a result of a miscarriage of one twin or multiple. The fetal tissue is absorbed by the other twin, multiple, placenta or the mother. This gives the appearance of a “vanishing twin.”

 

Answer:

 

If twins have two separate placentas, live cells from twin A cannot reach twin B.  If twins share the same placenta, blood cells from the affected twin can enter the vessels from the healthy twin. Although these blood cells may live for some time they cannot change the genetic code of the healthy twin. It is like a woman who receives a blood transfusion from a male donor – she will not obtain any genetic characteristics of her donor. 

 

Q: Can one normal chromosome compensate for deleted chromosome - such as in girls and Fragile X Syndrome?

The reason that Fragile X is different than an autosomal (pairs one through 22) deletion is because of a process called lyonization. In effect, one X chromosome in every cell is randomly turned off, so that at any time, only one X is actually functional. This is not the case for non-sex chromosomes and doesn't happen in males, who have only one X chromosome. For non-sex chromosomes (the autosomes), if one whole chromosome were missing, the resulting embryo would miscarry or that particular egg or sperm would not be viable and would not be involved in conception. We can survive with small amounts of genetic material missing or extra, but usually missing or extra genetic material causes some kind of birth defect, inherited disease or other problem.

Robert Wallerstein MD

Q: Can you provide more infertility resources?

Resolve.org (the National Infertility
Association) http://www.resolve.org

Q: Cancer Risk: What is the increased cancer risk in those with chromosomal abnormalities?

The issue of increased cancer risk in children with chromosomal variations is not clear. There are many genes associated with the process of cancer development. Cancer occurs as a loss of control of cell growth. Most cancer occurs as an acquired process. This means that a person is not born with the genetic change to create loss of cell growth control, but through time-the normal aging process, changes or mutations occur in the genetic material. We think about this as a 2 step or 2 hit process. One change happens in a cell and then it takes a second change to put the cancer into motion. If a person is born with a chromosomal variation then he or she may have the first hit already and therefore be at increased risk by virtue of the fact that it will only take one more hit to cause the cancer to begin developing. This scheme was developed in regard to retinoblastoma, a cancer affecting the eye. Anyone can bet retinoblastoma. Children with a deletion of chromosome 13 in the right region, are at increased risk for developing the tumor because they only need one more hit.

Typically, we see the increased cancer risk in certain regions with certain known genes. It is usually associated in individuals with a deletion of that region. There are tumor suppressor genes that stop tumors from developing. The loss of these genes causes a loss of tumor suppression and can give some risk to increase tumor beginnings. In people with extra chromosomal material, this increased risk is less common as typically, there is no loss of function.

In following children with chromosomal rearrangements, data is new and evolving. In years past, many children with chromosomal variations did not survive early childhood. It may not be known how chromosomal variations affect much older people. There are no good natural history studies on many chromosomal variations. These are questions waiting to be answered.

There are certain regions with a specific cancer risk. In our practice, we had one child with a chromosomal variation and a cancer. We know that there is a relationship, but the question is what to do with that information. If a specific risk is known form a site, then surveillance is appropriate. For example, if a child has a deletion of a known cancer gene, then testing for that specific cancer at periodic intervals makes sense. If there are just non-specific cancer genes in a region, it is hard to know what to do if anything about that. There is no substitute for having a good pediatrician and investigating anything in the way of symptoms that is unusual. The cancer risk conferred by chromosomal variations in general is probably small outside of a few isolated cases. That may not be such a specific answer, but that is how I think about it.

I think that it is important for parents to discuss with their genetics professionals if there is any known cancer risk associated with their chromosomal variation to see if any increased surveillance is needed. Things such as imaging studies might be suggested. For most, there really is not increased risk. Hopefully, addressing this issue with the genetics professionals will allay any fears.

Donna Wallerstein
Certified Genetic Counselor

Robert Wallerstein M.D.
Medical Geneticist


Q: Cannot find any information on my child's chromosome deletion

It is often very difficult to predict the effects of a chromosome deletion because some deletions are very rare. In addition, even for those rare deletions that appear to be exactly the same, there might be very subtle differences that could cause differences in the clinical effects of the deletion. While there might not be much information about this particular deletion, it is recommended that the family be referred to a genetic counselor so they can better understand the significance of the deletion.

Michael Graf
CDO Medical Advisor
Certified Genetic Counselor


Q: Cause of chromosome deletions

Unfortunately we do not know what causes chromosomal deletions. We think that something happens during the process of formation of the egg or the sperm or during the process of fertilization, although the egg and the sperm would probably look "healthy". There is no evidence to suggest there is some sort of environmental cause such as infections or other exposures. And, when the parents' chromosomes are normal, the chance of the deletion occurring again in another child is extremely small (less than 1%). So we assume that the mechanisms in the cell for duplicating and dividing up the chromosomes is imperfect; sometimes whole chromosomes or pieces of chromosomes can "get lost". We consider this to be a random, accidental sort of thing. I apologize that this explanation is probably not very satisfactory. However, our understanding of this matter is quite limited.

Karen Heller, Certified Genetic Counselor

ADDENDUM: For the most common microdeletions, there are genomic hotspots-the architecture of the genome makes these regions more prone for deletions.

Shashikant Kulkarni Director, Clinical & Molecular Cytogenetics, Laboratory & Genomic Medicine


Q: Cerebral palsy & chromosome deletions: Are children with deletions more at risk for CP? Why would a genetic disorder cause CP?

Cerebral palsy is just a description, sort of like saying that someone
sneezed. You don't know why they sneezed - could be allergies, pepper,
catching a cold.... - lots of reasons. Same with CP; it just describes
what the therapist is seeing, some spasticity or perhaps one side is
more hypertonic than the other. Any time a child has a chromosome
problem, any
constellation of problems is possible. We do tend to attribute every
symptom to the chromosome finding, whether it is related or not. In
general, I tend to think of CP as more a "birth accident" kind of thing
because lots of kids who lose oxygen at or near the time of birth have
CP.
Certainly kids with chromosome problems can also appear to have CP or CP
like findings because again, CP is just a descriptive phase and not a
diagnosis on its own. Hope that helps,


Donna Wallerstein, MS
Certified Genetic Counselor


Q: Child with difficult to diagnose medical problems - doctor has not seen this before and has no suggestions

1) Just because the geneticist couldn't figure it out the first time, doesn't mean s/he won't figure it out a year or so later, when your child has grown and changed a bit, or when the doctor has learned something new. So go back for a follow-up visit.

2) Consider consulting another geneticist, even if you have to travel - to find one, go to "acmg.net" and use the "find a geneticist" function. Doctors expect you to seek 2nd opinions, especially when it's a tough case.

3) Ask the geneticist to review the chromosome report: how long ago was it done and which lab performed it? Perhaps it should be repeated? Perhaps there is a "FISH" test that can be added?

4) Ask the geneticist about chromosomal micro-array testing or "CGH" - this is a newly-developed test (still somewhat controversial and not widely available) that can detect very tiny chromosomal imbalances that may not be detected by a routine chromosome analysis.

5) Have you consulted a pediatric endocrinologist (hormone doctor)? Some of the things you describe (like hirsutism and excess growth) could be related to hormonal problems.

6) I would make periodic appointments with a geneticist, but in the meantime, if no diagnosis is available, just focus on the problems at hand and deal with each of them as best you can. For example, make sure she is receiving good care for her seizures; make sure she is receiving appropriate school services; etc. Although it is preferable to know what the diagnosis is, in the end, you still have to deal with each of her problems in just the same way as you would any other child with that same problem. And even if you learned that she had a particular rare diagnosis and you found 1 or 2 other children with the same thing, I assure you, each of them would have somewhat different problems - no two children are alike. Good luck to you and your daughter!

Karen Heller
Certified Genetic Counselor


Q: Choroid Plexus Cysts: I am pregnant and an ultrasound showed 2 bilateral CPC on the baby? No other abnormalities were present. Should I worry?

Choroid plexus cysts are associated with chromosome anomalies in 1% of cases. The vast majority of individuals are NORMAL. It can be a normal finding. Overall, we are reassuring.

Robert Wallerstein MD
Medical Geneticist

 


Q: Chromosomal microarray analysis.

A chromosomal microarray (also known as a microarray-based comparative genomic hybridization test) is a new advance in genetic testing. The scientific advance is that this single test will detect a large number of known chromosomal deletions (loss of genes) or duplications (gain of genes), such as 22q11 deletion, Williams Syndrome, Smith-Magenis
Syndrome, etc. The test is called a microarray because, at the
microscopic level, pieces of DNA called "clones" are arrayed on a glass slide. The patient's DNA is then "hybridized" to the pieces of DNA on the glass slide, and missing or extra pieces are detected. In current versions of the microarray, there are about 850 clones, and these cover about 100 different known deletion or duplication syndromes. Recall that a chromosome is essentially a very long piece of DNA, which is supercoiled and held together by structural proteins.

It is important to realize that such new technology as the microarray, in addition to detecting known genetic diagnoses, can also detect differences in DNA that may or may not have any medical or developmental consequences for the child or family. This is why a clinical geneticist should interpret any abnormal results. It is often helpful, in the case of an uncertain microarray test result, to test the parents to see if one of them has the same DNA difference observed in the child. If the parent is unaffected by the child's condition, then this is taken as evidence that the test result is probably a benign DNA difference and not a true pathological deletion or duplication of DNA.

The chromosomal microarray is now considered by clinical geneticists (physicians specializing in genetics) to be a standard medical test for all children with developmental delay, autistic spectrum disorders, the presence of multiple congenital anomalies (multiple unexplained physical problems at birth). In addition, the microarray can be applied to diagnosis of fetal anomalies, using samples from amniocentesis or chorionic villus sampling during pregnancy. It costs about $1500, and is typically covered by insurance companies when clinically indicated. Baylor College of Medicine Medical Genetics Laboratories
(http://www.bcm.edu/cma/proPostnatal.htm) is a well-established provider of this technology (1-800-411-GENE), although there are others as well, and I do not necessarily endorse any particular laboratory. The technology is essentially the same in all laboratories that offer chromosomal micorarrays. Thomas Morgan, MD Washington University School of Medicine St. Louis Children's Hospital

Q: Chromosome 9 Inversion - Normal Variant

Pericentric inversion of one chromosome 9 [inv(9)(p12q13)] is considered a polymorphic variation and is one of the most common forms of autosomal inversion diagnosed prenatally and postnatally. We come across this variation quite frequently and regard this as nothing but a polymorphism. With the knowledge we have today, we can be confident that this variation is clinically benign. We continue to learn more about these and other variations and their possible effects if any. I agree with the genetic counsellor that there is no need for the parents to be tested for this variant.
Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
CDO Medical Advisor


Q: Chromosome analysis accuracy: original diagnosis now has proved to be inaccurate: is cytogenetics subjective?

We have had similar situations where a chromosomal rearramgenet has been
re-evaluated later with a change of breakpoints. Clearly, if you are trying
to find a near exact match in terms of comparison cytogenetically, this is
frustrating. As you say cytogenetics is somewhat subjective. The bands on
the chromosomes are numbered and it is very systematic in how the bands are
described. However, when there is a deletion or rearrangemnt, it may be
difficult to determine the exact bands involved. For example, the same dark
band can appear to be very different when the light band nearby is deleted.

The advent of FISH as well as other molecular techniques has made excellent
adjuncts available to the cytogeneticist. These are often used to help
analyze a particular deltion to describe it more accurately. Please keep in
mind that these techniques improve the resolution, but even deletions that
are apparently the same may be different on a molecular level. The gene
mapping technique is not done on a routine clinical basis, but more for
researchers trying to understand a particular region. This is very labor
intensive even more so than routine chromosomal analysis. Genes are still
below the level of resolution of cytogenetics. One band difference implies
a difference of hundreds of genes. We know that a single gene can make a
world of difference in an individual's development. So even with the same
cytogentic karyotype, there may be differences. This a large part of the
challenge of individuals with chromosome rearranegments. There is so much
variability. We can draw commonalities, but each individual is unique.

Robert Wallerstein
Medical Geneticist


Q: Chromosome Micro Array (CMA)

Chromosomal Microarray Analysis (CMA) is a new molecular cytogenetic test designed to detect losses or gains representing deletions or duplications for a wide array of clinically significant regions of the human genome. The test will detect the great majority of the defined microdeletion and microduplication syndromes. However, CMA will not always detect balanced translocations, inversions, low level mosaicism or genomic imbalances.

Therefore if a routine karyotyping was not performed prior to or concurrently with CMA, it is recommended. In addition, gene mutations, uniparental disomy, imprinting defects, epigenetic mutations or small genomic imbalances such as intragenic deletions or duplications will not be detected by microarray.


Q: Chromosome Translocation - Probabilty of Recurrence

A chromosomal translocation such as this clearly must have occurred at a specific moment in time, during the division of a specific cell, most likely a sex-specific cell that was responsible for producing either egg cells (in the maternal ovaries) or sperm cells (in the paternal testes).

"Mosaicism" or "gonadal mosaicism" are terms that refer to the theoretical risk that some variable percentage of maternal egg cells or paternal sperm cells contain the same translocation that was observed in a child born to that couple.

Unfortunately, we are unable to tell parents what percentage of their egg or sperm cells contains the translocation, and so geneticists must provide rough estimates, ranging from less than 1% to a few percent probability of recurrence, averaged across many couples. Any particular couple may have a much higher or much lower probability, however, depending on the percentage of abnormal egg or sperm cells.

Dr. Thomas Morgan
Medical Geneticist


Q: Chromosome Translocation 16;21 Carrier and Pregnancy

There are several possible outcomes for a pregnancy: 1) Totally normal chromosomes 2) Balanced translocation - just like the mother - expected to be healthy, but with possible future reproductive problems 3) Unbalanced translocation - this could involve deletion or duplication of chromosome 21, deletion or duplication of 16p (short arm), or deletion or duplication of 16q (long arm). Most of these would result in a miscarriage, but a duplication of chromosome 21 ("trisomy 21") would result in a child with Down syndrome, and duplication of 16p, I think, can result in a live-born baby with very severe abnormalities.

Figuring out the chance of each of these outcomes is very complex and would require analysis of this family's history. In almost all situations, though, if the pregnancy continues all the way to term (and does not miscarry), the chance would be very high that the chromosomes would be either 1) or 2) and the baby would be healthy.

CVS or amniocentesis could determine the baby's exact chromosome make-up during a pregnancy. If IVF is done, it may also be possible to perform PGD (pre-implantation genetic diagnosis) to select only embryos that are either 1) or 2). This would have to be discussed up front with an IVF specialist. It is quite costly, and I am not aware of any sources of funding for this.

Karen Heller
Certified Genetic Counselor
CDO Medical Advisor


Q: Chromosome X duplication effects

It is very hard to say what the exact effects of this duplication would be because in XX individuals (females), one X chromosome undergoes inactivation. Some females are completely protected from any adverse consequences of X duplications by inactivation; others may show all of the effects associated with trisomy for a large region of one chromosome. A very general statement is that cells do not grow or perform their specialized functions as well when there is an imbalance of genetic material, and brain cells are particularly susceptible to impairement by chromosome abnormalities because their function is so complex and specialized.

Andrew Zinn, M.D.
Medical Geneticist


Q: Chromosome X inversion - male vs female carriers

There is no risk for recombination in male inversion carrier as males have only one X, it does not have the opportunity to recombine to generate a duplication/deletion.

Female inversion carrier - if the baby is a boy a miscarriage could result if the inverted X recombined with the normal X because this would result in a large X chromosome deletion and duplication that is not viable.
If the baby is a girl, there is a possibly of live birth of a child with physical and/or developmental abnormalities.
Dr. Andrew Zinn
Medical Geneticist


Q: Chromosome X inversion carrier: can the breakpoints change from where they are in me to break other genes?

Answer: This does occur on occasion (probably rare) and can result in the same apparent chromosome abnormality having different effects in different relatives.
Dr. Andrew Zinn
Medical Geneticist
CDO Medical Advisor


Q: CP secondary to chromosome abnormality.

Is her deletion of chromosome 4 or chromosome 14? I wasn't clear from the email....

I find "cerebral palsy" an annoying term to be perfectly honest! To me, it conjures up 1950's images of people trying not to say "mentally retarded" or "handicapped".

Medical people SHOULD understand if you walk in say, "My child has a chromosome abnormality" - they may not always know the specifics of any given chromosomal problem, but they will at least have some general idea. The same information that you listed in your email would also be helpful for them to know: she has brisk reflexes in her arms and legs, but she has low muscle tone in her trunk. That is her baseline. This can be very helpful to a doctor just examining your child for the first time, particularly if you are there because she is sick, with a fever or other symptoms. Knowing that she has those kinds of findings on a good day helps them distinguish between symptoms because she is ill and symptoms that are just her.

For people in general, I would use whatever you feel comfortable with..."My child was born with a genetic problem; it causes her to have neurological impairment" or something to that effect. You can talk about her physical differences and/or her differences in learning. Usually, just a couple of sentences is enough for people to get the general idea.

Another thing that I find annoying is that sometimes people, even medical people, tend to hear the word "genetic" and mentally translate that into "hereditary". I can't tell you the number of times that people are referred because they have had a pregnancy or a child born with a chromosome abnormality that just occurred by chance and have been completely misinformed that they were at high risk for another child with the same kind of problem. If you are having a more lengthy discussion with people about your child, it can be very helpful to explain that your child's condition does not run in your family and just happened by chance.

I hope this is helpful to you!

Donna Wallerstein, MS
Certified Genetic Counselor

Q: Cri du Chat syndrome - band 14 deletion?

You stated that the deletion involves band 14, which could have two possible interpretations (your doctor can determine which one is correct): (1) the entire end of the short arm of chromosome 5, from band 14 to the tip of chromosome, is all missing; (2) only band 14 is missing, and the deletion was "interstitial," meaning that the tip of the chromosome was not lost.
If the first explanation is correct, and the entire tip of chromosome 5p including band 14 was lost, recent studies have shown that these children have tended to have an "average" level of developmental delay for the 5p- syndrome, meaning that they develop the ability to communicate with at least some words and perhaps short sentences. Children with larger deletions involving band 13 may be more severely affected, and some do not develop language. I must emphasize, however, that there is always a fairly wide range of developmental outcomes, and the chromosome diagnosis allows only for generalizations, which may or may not apply to your child. Careful monitoring of his or her developmental progress over his or her first year or two of life will provide you with much more information about his or her developmental potential than his or her chromosome diagnosis can provide.
If the second explanation is correct, and only band 14 is missing, then developmental delay may be even milder, and language expectations will tend to be higher, on average, in children with this diagnosis.

Thomas Morgan MD

Q: CVS & mosaic balanced translocation.

I certainly understand your worry about the result of the CVS test, which showed 17% of cells having an "apparently balanced" translocation between chromosome 1 and the short arm of the X chromosome. However, this result is difficult to interpret, and its clinical implications (or lack thereof) will hopefully be clarified with time and further studies.
First, an amniocentesis can confirm or fail to confirm the result from the CVS, which sampled the baby's side of the placenta. As you mentioned, the likelihood of the CVS result being confined to the placenta (and not the baby) is completely unknown, because this finding is not frequent enough to permit any statistical generalizations. In other words, it is best to say it is possible, but with an unknown frequency, for the amnio not to demonstrate the X;1 translocation.
Next, a detailed ultrasound will be performed. We have no strong reason to suspect that it will be abnormal at this stage consider two facts: (1) the chromosome translocation was present in only 17% of fetal placental cells (reducing the risk of abnormality); (2) we don't know that the translocation resulted in damage to any particular gene (1 in 500 individuals has a balanced translocation, and only about 5% have a clinical abnormality as a result).
Unfortunately, you must wait for more information, as hard as that will be. However, I am cautiously optimistic (and hope that what I have written will take some of your concern away). It is always impossible to make a guarantee to any expectant couple that everything will be OK with the baby, with or without a chromosome result such as you have described. Some degree of worry is to be expected in all mothers; the CVS finding really should not add much to the universal level of maternal concern that you would still feel if the CVS had been "normal". I realize that that is not how worries operate, but I do hope you see the rationale in what I'm writing to you.
If any concerns emerge about the baby's physical or ultimate cognitive development, then you will be left with some doubt about the potential connection with the chromosome result. In that case, it would be possible to investigate the result further, by fine-mapping the precise spots where chromosomes X and 1 broke and traded genes. If a particular gene is damaged, that makes it likely that the chromosome translocation was the cause of any potential developmental issues, but as mentioned above it is premature to even think about that yet. I certainly wish you and your family the best as you wait for more information. Sincerely, Thomas Morgan, MD Dept. of Genetics and Yale Child Study Center Yale University
>

Q: CVS miscarriage rate - balanced translocation w/ symptoms.

Your main question, as I understand it, is how to interpret the finding, in your daugher who has speech and motor development delays, of an apparently balanced chromosome (4;9) translocation with an inversion (4), given the knowledge that her father carries this same diagnosis. I assume that he had no such delays in his development. In addition, there may or may not be others on his side of the family with this same chromosome translocation, depending on whether one of his parents also had it. The topic of the reproductive risks to the extended family (i.e., having a child with an unbalanced translocation), should be covered in a face to face genetic counseling session, if it has not already been addressed.
To answer your question more directly: we expect, 95% of the time, that a balanced translocation will not result in any developmental or medical consequences for the child. When we see that an unaffected parent has it, too, then we must assume that it is not the cause of the child's developmental delay, and other causes must be sought out. I hope this information is helpful to you. You also asked about chorionic villus sampling. The risk of a miscarriage is about 1 in 150 with this procedure, on average. I certainly wish you and your family all the best. Sincerely, Thomas Morgan, MD Washington University School of Medicine St. Louis Children's Hospital

Q: Deletion diagnosed prenatally - is there reason for concern if parent has the same deletion

Was FISH done to characterize this deletion?

It can be “assumed with near certainty” that there is usually no concern of abnormality, if the deletion is similar (thoroughly characterized by FISH in both the fetus and the carrier parent). As always there are very very rare exceptions when “similar” looking deletions are complex and differ at molecular level. So it is impossible to be 100% confident even if the deletion is found to be familial.

Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
Assistant Professor of Pediatrics
Genetics & Genomic Medicine


Q: Deletion diagnosed with amnio?

Possibly, but only if the deletion was easily visible by looking under a microscope at the chromosomes. If it was not visible, and had to be detected by a technique called FISH, then it would not have been routinely detected on amniocentesis. Even when deletions are visible by a light microscope, they are not always visible from an amniocentesis, because the quality of the cells from amniotic fluid are often not quite as good as cells from a blood draw after the
baby is born. The chromosomes may come out looking a bit shorter and not as
clearly defined.
Thomas Morgan MD
Medical Geneticist

Q: Deletions caused by environmental factors?

No. Environmental factors are not related. Deletions are random events that occur when parental chromosomes, during egg cell or sperm formation, pair up and exchange genetic material. This process, called "crossing-over," is essential for creating the genetic diversity that makes every person completely unique.

Thomas Morgan MD
CDO Medical Advisor

Q: Deletions occur as a result of deletion in sperm or egg?

A deletion can occur prior to fertilization, during the process of egg cell or sperm formation, or sometime after fertilization (in which case only a percentage of cells will show the deletion) this will not necessarily be detected on a karyotype of blood cells, but there is no indication for doing additional studies. If it occurred prior to fertilization, there is theoretically a small risk (<1%) of the deletion occurring in a subsequent pregnancy, because it may not have been only a single egg or sperm cell with the deletion.

Thomas Morgan MD
CDO Medical Geneticist

Q: Dental Issues: What about dental issues in kids with rare chromosome disorders?

Compiled by Penny Richards, turley2@earthlink.net

INTRODUCTION:
Though they may seem a minor concern next to heart surgeries and developmental delays, teeth are so important for eating, breathing, speaking, symmetrical facial structure, etc., that it's worth at least trying to stay on top of your child's oral health. In this FAQ, you'll get the distilled advice of the CDO parents on many subject concerning dental/oral health and hygiene.

Disclaimer: The following advice is culled from parent-to-parent postings on the CDO listserv. It should not be understood as a substitute for medical or nutritional advice from trained personnel.

TOPIC GUIDE:
BASIC ORAL CARE
BABY TEETH
DIET, FEEDING, AND ORAL HEALTH
DENTISTS
DENTAL SURGERY


BASIC ORAL CARE
Q. Why does my child have such weak teeth? Is it part of the chromosome disorder?

A. It's hard to say, but it is common for kids with chromosome disorders to have dental problems. There are many factors that contribute: there may be a basic congenital weakness in the structure of the teeth (for example, an insufficient quantity of enamel to protect them)just as there are congenital structural differences in other body parts. This can be worsened by environmental factorsour kids are often exposed to more powerful medications than other children, drink from bottles longer, consume sugary supplements for the extra calories, and have problems with oral defensiveness and self-care skills that make effective brushing a challenge. If breathing or feeding are also difficult for your child, the adjustments made to accomplish those necessary tasks (breathing through the mouth, for example) may further exacerbate decay in the mouth.

Q. How do I brush my son's teeth? He's very reluctant to let us into his mouth for any reason, and is not willing or able to brush his own teeth.

A. Many parents report success using electric toothbrushes (there are many models now available). There are several benefits cited: more efficient brushing, more consistent oral stimulation, and some kids like the buzzing sound and vibration involved. Ask your dentist or therapist if this is a good option for your child. Also, some dentists will provide you with a "bite block"a firm, foam tool that is inserted between the child's front teeth to keep the reluctant mouth open as gently as possibly. (This is also a useful item when administering some medications orally.) If your child must be restrained for toothbrushing, and you don't have two adults available, try wrapping his body in a large towel (to keep his arms from interfering).


BABY TEETH
Q. Will my newborn with a chromosome disorder get her first set of teeth later, just as she's growing more slowly than a typical child?

A. Not necessarily. Some families report delays in the eruption of baby teeth; others say they came right on schedule. Same with losing the baby teethsometimes it happens around age 6, as is typical, but sometimes it's delayed by as much as a few years. In addition, you may find that the order of erupting and falling out is not typicalmaybe a side tooth will come in first, or one or more teeth seem to be missing and never erupt.
Occasionally a child will have fused teeth, or other anomalies. Dental xrays can determine the state and number of the unerupted teeth, if this is troubling you or the doctors.

Q. My kindergartner has his first loose toothbut he can't talk, and I'm worried he'll swallow it when it falls out, without telling me. Isn't this dangerous?

A. Surprisingly, it's not usually dangerous to swallow a baby tooththey're made of pretty soft material and stomach acid is very effective in dissolving the sharp edges (same goes for small coins, they say). But if your child has swallowing or digestive problems, it might be worth mentioning this question to your pediatrician and dentist. Some dentists will let you to bring the child in when a tooth is very loose, and they'll pull it quickly, to save you from worrying "when?".


DIET, FEEDING, AND ORAL HEALTH
Q. How do I balance my child's need for extra calories with her risk for cavities?

A. Discuss your concerns with doctors, nutritionists, and dentistssometimes, the experts only see "their" part of the picture. If a medical professional recommends, for example, adding chocolate syrup to a baby's bottles for extra calories, that might not be in the child's best dental interestsask directly, is this worth the cavities it might cause?
Many of our children use dietary supplements like Pediasure or Ensurethese can be very sugary. Some parents dilute the supplement with milk or baby formula to minimize the harm. Remember also that there are many ways to increase calorie intake that don't involve sugarfoods higher in fat being the most obvious. A nutritionist can help you with ideas there.

Q. My child does not take nutrition or hydration orally. Are her teeth still at risk?

A. It is common to assume that such children will have fewer dental problems, but the fact is they just have slightly different oral health issues. The teeth still exist in a warm moist environment conducive to decay, and still need regular brushing to be kept clean. The gums are still prone to swelling in response to some medicationsbe sure to check often for bleeding or puffiness.


DENTISTS
Q. How do I find a dentist for my very young and/or very medically complicated child?

A. Ask your pediatrician for a referral to a dentist willing to see special needs children and VERY young children, and while you're at it, find out whether your insurance will cover such a visit (some won't cover dental appointments for under-2s). Alternatively, you can talk to other parents of special needs kids, or ask your child's case coordinator. Some teachers and therapists (especially those who deal with oral-motor issues) may also have leads for you. And occasionally parent support groups will invite a dentist to come speakthat might be another way to find someone for your child.


DENTAL SURGERY
Q. My child's dentist wants to do a few crowns and fillingsin the hospital! Is this common?

A. It is very common (and prudent) for dentists to prefer working under general anesthesia when there are likely to be serious risks with in-office sedation techniques. If your dentist is concerned about heart or breathing being interrupted, or suspects that your child may not respond typically to nitrous oxide or chloral hydrate, they will probably feel safer doing the necessary work in a hospital with an anesthesiologist and other supports available.

Q. Is this surgery going to be a logistical nightmare?

A. Scheduling a day surgery for dental work in hospital can be a HASSLE, but if you juggle the authorizations right, you can get the OR time and anesthesia covered by your health insurance, and the dental work covered by your dental insurance (assuming you have that). You may also take this opportunity to schedule a second procedure best done under general anesthesiasome parents have arranged for blood draws and hearing tests in conjunction with dental surgeries, for example. That might make the financial bite easier to justify. (Answered from the American perspective that assumes private insurance as a normparents in countries with national health coverage have a different system to negotiate. Additionally, some families may qualify for special public or charitable funding to deal with necessary dental workthese programs vary from state to state and country to countryask your caseworker if you're wondering what your options are.)


Q. Won't she look funny with a mouth full of silvery crowns?

A. People, especially other children, may notice your child's dental work.
Like all noticeable differences, it may prompt questions from curious strangersyou'll learn to answer these in your own way, just as you probably already answer other questions about your child's visible differences. And remember, the appearance of crowns may be unusual, but it's better than the appearance of a mouth full of decay. If the crowns will be very visible, ask your dentist if they can use a material that looks more "tooth-colored."

Q. Any other tips to prepare for this surgery?

A. Be sure to discuss ALL physical differences with the dentist AND the anesthesiologist before the surgeryeven if it doesn't seem relevant to dental surgery, mention it anyway just to be safe. Be sure to discuss antibiotic prophylaxis with the dentist before hand if your child has a heart defect. Expect to discuss the worst case scenarios with the doctor and anesthesiologist right before the surgery. They will tell you that there are no guarantees; that sometimes with our kids there are complications no one could foresee; that they may call off the surgery suddenly, if the anesthesiologist can't establish an airway. In short, plan as you would for any surgery, and don't assume this is "just minor"especially the first time, you'll probably experience much the same anxiety and fear as any parent before ANY surgery on her child.


A FINAL WORD:

Don't blame yourself for a child's disappointing oral health. Your hard work can minimize her need for intervention, but it probably can't be eliminated entirely. Even typical kids get cavities, right? Do your best to follow dentists' recommendations, and don't put off checkups or surgeries.


Q: der (X) X;Y unbalanced translocation - baby girl - SRY gene absent, SHOX deleted

The karyotype indicates that the Y chromosome material has replaced a small piece of the short arm of the X. Since the SRY gene was absent, the baby will definitely be a girl. She may have short stature that can be treated with growth hormone and could have some issues with ovarian function. Both of these problems are managed by a pediatric endocrinologist, and I recommend the parents seek a referral to an endocrinologist after the girl is born.

SHOX gene is most likely deleted. That's why I mentioned short stature as a possible outcome. There is a chance of the wrist problem, known as Madelung deformity. In our experience, it is uncommon and usually mild with this particular type of SHOX deletion. There is nothing to do but watch and wait - if it occurs (often around the time of puberty) and is symptomatic, surgical correction is an option. Same goes for short stature - wait and see.

Andrew Zinn, M.D.
Medical Geneticist


Q: Diabetes & Liver issues with 1p36 deletion

Sugar (i.e. diabetes) and liver issues would definitely not be a cause of the chromosome 1p36 deletion. If the question was whether the 1p36 deletion could cause sugar or liver issues, these issues are not the most common health problems described with 1p36 deletion. However, chromosome deletions have been associated with a large array of health problems and these health problems can vary from individual to individual, even with the same apparent deletion. In addition, these issues, especially sugar issues (diabetes) are very common in people without a chromosome abnormality so it may be difficult to determine whether they are related to the 1p36 deletion. I would recommend speaking to a geneticist and/or a genetic counselor to learn more about these medical conditions and to help determine whether they might be associated with the 1p36 condition.

Michael Graf Certified Genetic Counselor
CDO Medical Advisor


Q: Diagnosing Wolf Hirschhorn Syndrome

WHS is diagnosed by clinical evaluation of characteristic dysmorphic features and by performing cytogenetics and FISH studies. Some of the patient have a cytogenetically visible deletion (identified by classical cytogenetics) with varying breakpoints on the short arm of chromosome 4 at 4p16.3, others have a cryptic deletion requiring FISH (fluorescent in situ hybridization) to make the diagnosis. Hope this helps.
Shashikant Kulkarni
Director of Clinical & Molecular Cytogenetics
CDO Medical Advisor


Q: DiGeorge Syndrome - risk of having another child with this disorder?

The diagnosis must be confirmed by FISH showing a deletion of 22q11 in the child, and both biological parents must have FISH testing showing they lack the deletion. In addition, both parents must be examined by a clinical geneticist, and found not to have the physical characteristics of 22q11 deletion. If all of that is done, and is reassuring, then there is still a slight (probably <
1%) chance that one parent may transmit the deletion again, due to "mosaicism" for egg or sperm cells with the deletion. Thomas Morgan MD Medical Geneticist Yale University Medical Center.

Q: Discrepancy in Amnio Results, Low Level Mosaicism or Artefact ? PUBS

The PUBS gets a sample of blood from the umbilical cord and so it looks at fetal blood. The issue is to determine if there are any trisomy cells in the fetus. If the blood is normal, then the chance that there is something wrong with the baby is much reduced. Somtimes people get an additional sample of amniotic fluid at the time of the PUBs as it is easy to do.

Unfortunately, no one can ever give a guarantee that evrything is normal. The more normal test results, the greater the chance that the fetus is normal.

Robert Wallerstein MD
Medical Geneticist


Q: Do women really have old eggs?

Yes, the risk of whole chromosome disorders like trisomy 21 (Down syndrome) rises with increasing age of the eggs.
Andrew Zinn MD
Medical Geneticist


Q: Does a mother with Turner's Syndrome mosaic (6%) have a higher risk of having a child with Turner's? Can she have a chromosomally normal child conceived naturally?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

Full Question:

I have Turner’s Syndrome mosaic (6%) with a healthy 4 year old son who was conceived naturally. Since trying for a second child, I have had an ectopic pregnancy, a missed miscarriage, and a D&E at 16 weeks due to the baby having triple x syndrome.  My question is, since I have mosaic Turner’s Syndrome and am now 4 years older since my son’s birth, is it worth it to continue trying naturally? Does my child have a higher risk of having Turner's?  Also, since i've failed my IVF cycle does this mean that conceiving a chromosomally normal child is a stretch? I would love to believe that natural selection is better and that maybe the meds just didn't work for me but i really don't know.  Any insight would be helpful, thanks in advance.

Answer:

You have 6% of 45,X (Turner’s Syndrome) cells in your blood, but we do not know the ratio between 45,X and 46,XX cells in your ovaries. However, only 46,XX cells may produce egg-cells suitable for fertilization. Women with a 45,X/46,XX karyotype may have difficulties conceiving, but their risk of having a 45,X child is the same as for 46,XX women. 

 
In my opinion, neither trisomy X and nor monosomy 16 are related to your 45,X/46,XX status. Basically, the incidence of nondisjunction (the mechanism leading to trisomies or monosomies) is increased after the age of 33 or 34.

Preimplantation genetic diagnosis is a very expensive and not very promising variant for a 45,X/46,XX woman of your age.  My advice: try to conceive naturally. If the embryo survives until 9-10 weeks, biochemical examination of the maternal BLOOD could be used to exclude all possible aneuploidies.

 


Q: Does every chromosome have a centromere?

There is almost always a centromere. IDIC is short for isodicentric and centric implies that there is a centromere. In rare cases there is no classic centromere, but something else then becomes a neocentromere.
Andrew Zinn MD
Medical Geneticist
CDO Medical Advisor


Q: Echogenic bowel: What is Echogenic Bowel?

Answered by Robert Wallerstein M.D. 

Echogenic bowel is an ultrasound finding with increased signal in the intestines. It is a normal variant that has a small association with Down syndrome, cystic fibrosis and some infections. It overall is usually a normal variant of pregnancy, but some testing is often advised due to the associations mentioned above.


Q: Explain 3q deletion syndrome.

Children have been identified with this syndrome, although there is a very wide range in the extent to which children are affected, some severe, and some much less so.
However, some common aspects of the loss of a substantial number genes on chromosome 3 include developmental delay, lack of speech, high arched palate and variable organ malformations (brain and skeletal malformations being the most serious and frequent). The deletion can occur for the first time in the child herself, or be inherited from a parent who has a balanced chromosome rearrangement, and so parents should be offered the opportunity to have their own chromosomes tested.

The National Library of Medicine has a brief description of findings in this syndrome (albeit with lots of technical terms), and it is found at: http://www.nlm.nih.gov/mesh/jablonski/syndromes/syndrome119.html

Thomas Morgan MD
Medical Geneticist

Q: Explain Caudal regression syndrome.

Caudal regression syndrome refers to incomplete development of the lower part of the body due to unknown, probably quite complex, causes. It usually does not recur in subsequent pregnancies to the same couple, with a few recorded exceptions. Maternal diabetes during pregnancy is considered a risk factor, and thus it is important to rule out, or to treat, maternal diabetes in subsequent pregnancies. There is no specific genetic testing for this syndrome. However, it is typical for a chromosome analysis to be done on affected infants or fetuses.

Thomas Morgan MD
Medical Geneticist

Q: Explain de novo X;autosome translocations.

Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49: 995-1013, 1991.


A questionnaire sent to major cytogenetics laboratories in the United States and Canada over a 10-year period collected data on the frequency and outcome of cases with either apparently balanced de novo rearrangements or de novo supernumerary marker chromosomes detected at amniocentesis. Of 377,357 reported amniocenteses, approximately 1/2,000 had a de novo reciprocal translocation, 1/9,000 a Robertsonian translocation, 1/10,000 a de novo inversion, and 1/2,500 an extra structurally abnormal chromosome of unidentifiable origin. The risk of a serious congenital anomaly was estimated to be 6.1% (n = 163) for de novo reciprocal translocations, 3.7% (n = 51) for Robertsonian translocations, and 9.4% (n = 32) for inversions. The combined risk for reciprocal translocations and inversions was 6.7% (95% confidence limits 3.1%-10.3%). The risk of abnormality for extra nonsatellited marker chromosomes was 14.7% (n = 68), and that for satellited marker chromosomes was 10.9% (n = 55). In non-Robertsonian rearrangements, distribution of breakpoints among chromosomes was not as would be expected strictly on the basis of length. Most breaks were stated to occur within G-negative bands, but there was little evidence of particular hot spots among these bands. Nevertheless, there did appear to be a correlation between those bands in which breakage was observed most often and those bands where common or rare fragile sites have been described.


As you can see, Dr. Warburton cited a risk of 6.1% for “a serious congenital anomaly”. I do not have the whole paper handy; maybe in the body of the paper she mentions something that would be closer to 10%.

In the course of researching this followup question, I came across a very recent paper in Clinical Genetics (Abrams L, Cotter PD. Prenatal diagnosis of de novo X;autosome translocations. CLIN GENET 65 (5): 423-428 MAY 2004) that claims that the risk for prenatally diagnosed de novo balanced X-autosome translocations is much greater than for balanced translocations in general, perhaps as high as 50%. They suggest this could be due to X-linked recessive diseases, X inactivation, etc. However, in my opinion their estimate is exaggerated by the bias toward publishing and reporting those cases with anomalies. I will continue to research the matter and let you know if I find any additional relevant studies.

Andrew Zinn MD
Medical Geneticist


Q: Explain Encopresis.

Encopresis is defined as repeated voluntary or involuntary passage of stool into inappropriate places. It is classified as primary when a child has never achieved bowel control and secondary when a child has achieved regular control but has discontinued that behavior. It is a common problem in pediatrics affecting as many as 3% of all children. In children with chromosomal problems, this is more common.

Encopresis can have a behavioral/psychological cause as well as a medical cause. The medical issues associated with fecal soiling without retention of stool include: diarrheal disorders, central nervous system dysfunction, sensory or motor deficits in the anorectal or pelvic floor muscles. Chronic retention of stool with with or without soiling can include: Hirschsprung;s disease (lack of nerve cells in the colon), intestinal pseudo obstruction syndrome, hypothyroidism, hypercalcemia, chronic codeine or phenothiazine use, disorder of the intestinal smooth muscle, and anal/rectal stenosis or fissure.

The evaluation of this problem requires a complete developmental and social history as well as a thorough physical examination including rectal examination and neurologic examination. Urinalysis and urine culture is often important to rule out infection. X-ray of the abdomen to look for retained stool may be necessary. In some cases rectal biopsy is needed if there are signs to suggest Hirschsprung disease.

Often encopresis is the result of chronic constipation. A complete bowel clean out to try to return a lost physical sensations and muscle tone in the colon. Often times the treatment is a slow process of changing bowel habits.

The evaluation by a gastroenterologist is an important step. The treatment are often effective, but keep in mind that progress is many times slow.

Robert Wallerstein MD
Medical Geneticist
CDO Medical Advisor




Q: Explain Isochromosome Yp.

Isochromosome Yp. This is a relatively rare condition. As your doctors have already said, a high risk of infertility may be predicted, but it would be inappropriate to make long-term projections about his developmental potential, based solely on his chromosome diagnosis. What you can carefully observe about him is far more important in terms of predicting how he will do in the near future. Clearly he has some delays in speech development, but we don't know how he will do going forward. In my opinion, what he needs most of all is a pediatric endocrinologist who will watch him closely for any signs of male hormone insufficiency, as well as a developmental pediatrician or other specialist who will identify specific needs in his educational program. He should also have a clinical geneticist who sees him periodically to ensure that everything that should be done for him, is being done. I hope that this information is helpful to you, and that it makes practical sense. I wish you and your nephew the best. Sincerely, Thomas Morgan, MD Dept. of Genetics/Yale Child Study Center Yale University


Q: Explain more about Triploidy.

Triploidy is a chromosomal abnormality where three complete sets of the haploid genome instead of the normal two sets are present. In other words, in humans there are 69 chromosomes instead of the normal 46 chromosomes. One of the causes of triploidy is double fertilization of a normal egg, resulting in an extra set of paternal chromosomes (dispermy). Triploidy has been estimated to occur in 1-2% of all clinically recognized pregnancies. However, the majority of triploidy conceptuses do not survive to term. It has been assessed that only one-third of triploidy conceptuses survive past 15 weeks. Triploidy has been reported in 1-13% of miscarriages that were studied. The recurrence risk for triploidy is about 1%. In other words, there is about a 1% chance for you to have another pregnancy with triploidy, regardless of whether the extra set of chromosomes came from the mother or the father (depending on your age, there may be an increased risk for you to have a pregnancy with extra or missing chromosomes, such as those that result in Down syndrome).

Amy Sturm Certified Genetic Counselor

Q: Explain Normal Variants.

Normal variants:

1qh
9qh
16qh
Yqh

The above four variants are different between individuals in that they have different amounts of heterochromatin (h) on the long arm (q).

Inv(9)(p11q12)
Inv(9)(p11q13)
Inv(1)(p11q12)
Inv(1)(p13q21)

The above four "inversion variants" involve inversions of the heterochromatin of the number 9 and number 1 chromosome.

t(Y;15)
t(Y;22)

The above two translocations involve the translocation of heterochromatin from the long arm of the Y onto the short arm of the acrocentric chromosome (15 and 22).

This final list (below) includes both duplications and deletions that appear to be variants. However, when one of these deletions or duplications is found in an individual, before it is determined to be a variant of no pathological significance, it should be proven to be present in a normal individual within the same family.

Duplications:

1p21-p31
1q42.11-q42.12
9p13
9q13-q21
15q12-q13
16p11.2

Deletions:

5p14.1-p14.3
11p12
11q14.3
13q21
16q21

This section above is based upon information from:
Chromosome Abnormalities and Genetic Counseling, Second Edition, Gardner and Sutherland




Q: Explain paracentric inversions & affected children.

With paracentric inversions, the risk for an abnormal liveborn is low, but it can happen, therefore, prenatal testing by amniocentesis or CVS would be an option as well as level II ultrasound to see if the baby inherited an abnormal set of chromosomes (amniocentesis and CVS) and to screen for birth defects (ultrasound). Individuals with paracentric inversions may also be at an increased risk for recurrent miscarriages.

Amy Sturm
Certified Genetic Counselor

Q: Explain PDD, seizures and 18q deletion.

Thank you for your inquiry to CDO. Although autism and pervasive developmental disorder have been reported in 18q deletion, I am unaware of a study giving a reliable estimate of PDD characteristics specifically. In one series, 1 out of 16 children (6%) met criteria for autism. The general consensus seems to be that at least some PDD characteristics would not be considered unusual in 18q, and mild PDD manifestations may be common. However, there may or may not be a difference in PDD symptoms between children with 18q and other children with similar degrees of developmental delay.
(2) The likelihood of a negative EEG in a child who is having apparent seizure activity is difficult to estimate. In large part, it depends on how frequent the seizure-like episodes are. If the child has these episodes during an EEG, and it is normal, an alternative explanation must be sought.
Thomas Morgan MD
Medical Geneticist

Q: Explain Recombinant.

A recombinant is the result of an event where chromosomal material changes places. When it does, the rearranged chromosome that results is called the recombinant. This can occur by different mechanisms and creates a new combination of genetic material.

Robert Wallerstein MD
Medical Geneticist

Q: Explain telomere FISH probes.

Subtelomeric probes are a relatively new addition to the arsenal of cytogenetic tests. This test is a collection of 41 different FISH (fluorescent in situ hybridization) probes that are used to identify rearrangements that cannot be seen on routine chromosome studies. The subtelomeric probes look at the regions right behind the ends of the chromosomes (telomeres) that are moved around if there is a submicroscopic rearrangement. Each of the probes is a different color so that the specific chromosomal segment can be identified. This is a very labor intensive process and is expensive. When there is material of unknown origin, this test can be very useful. It can also be used when a geneticist suspects a chromosomal abnormality and routine chromosomes are normal. Some studies report identifying previously undiagnosed chromosomal abnormalities in 5% of children with unexplained mental retardation. We are starting to use the test more in clinical practice. In fact, it was helpful in a recent family that we saw where a child had extra material on the p arm of chromosome 9 and this material turned out to be derived from chromosome 16. Without subtelomeric probes, we probably would not have come to that conclusion. As a new test insurance coverage may be variable and that may be the rate limiting step in performing in more frequently. The test is quite expensive near $1000 or more. Not all cytogenetic laboratories offer this test . Perhaps more will in the future. It is the up and coming addition to chromosome analysis.

Dr. Robert Wallerstein, Medical Geneticist
Donna Wallerstein, Genetic Counselor


Q: Explain the 2q banding pattern.

The resolution of chromosomes and how much detail (i.e. the banding
pattern) you see depends upon the band level of the chromosome analysis. At a 550 band level, which is very typical for a blood (tissues usually have a lower band level - not as good resolution), 2q is broken down into.........q21.1,q21.2.21.3,q22,q23,q24.1,q24.2,q24.3......... Thus, this child is missing the region of 2 from 2q23 to 2q24.2, which is actually a fairly small deletion.

Michelle Springer
Certified Genetic Counselor

Q: Explain triploidy & miscarriage.

Of all recognized pregnancies approximately 15-20 percent end as miscarriage, mostly in the first trimester. About half of such miscarriages have a chromosome abnormality. Your first miscarriage may have been due to a chromosome abnormality, but there is no way to know for sure. The recurrence risk for triploidy is actually thought to be quite low, or none at all.

Amy Curry Sturm Certified Genetic Counselor

Q: Explain Turners Syndrome 45X & 46 XY.

The chromosome test that your son had is not representative of his
chromosome makeup in his entire body. It only represents the blood
cells that were taken. His genetic makeup in other organs of his body,
such as the testes, may be represented by a different chromosome
distribution (for example, the 46,XY population of cells might be higher
than 8%). A website to get information on Turner syndrome is
http://www.turner-syndrome-us.org/.

It is also important to be aware that the presence of Y chromosome
fragments in patients with Turner syndrome is known to increase the risk
of gonadoblastoma and virilization. For this reason, the gonads may
need to be surgically removed. Y chromosome material is detected in up
to 6% of patients with Turner syndrome. Your son's pediatrician should
be made aware of this risk for gonadoblastoma.

Amy Curry CDO Medical Advisor, Certified Genetic Counselor

Q: Fetus & father have the same karyotype (chromosome duplication) - how confident should I be the child will be normal like the father?

If the baby's father has the identical chromosome, chances are high that the fetus will be normal. We have had such cases with us and there was a good outcome. There is some chance that the chromosome in the fetus while appearing to be the same as the father's is actually different on a molecular level.

Overall, the risks would be low.
Robert Wallerstein MD Medical Geneticist

Q: FISH + Microarray

With standard G-banding one may be able to see relatively large structural chromosome changes by examining the entire genome in one test.

With FISH one could examine individual loci (regions of interest) at a higher resolution (that means smaller changes ? deletions or duplications that are not visible by G-banding), but can only examine few loci at a time. Additionally one needs to have a prior knowledge based on the clinical presentation of the patient, as for which region should a FISH test be performed.

In contrast to this, an array is the best available method to perform several FISH tests, spanning the entire genome (if this is whole genome) or targeted region of the genome (targeted to regions which are known to cause a genetic disorder) at a higher resolution, more sensitive, and specific than a FISH test. However, an array will not detect balanced rearrangements in the genome. For the balanced rearrangements one needs to still do standard G-banding (Karyotyping).

Vaidehi Jobanputra, Ph.D.
Assistant Professor
Columbia University Medical Center


Q: FISH: Our doctor is fishing our only certain chromosomes-one at a time? Is there some way to check all the chromosomes at once?

FISH is a very specific procedure where DNA probes are used to detect whether or not a specific piece of DNA on a chromosome is present or not. With our current technology, you can only FISH for one deletion at a time. Geneticists will start out with a deletion that is most likely based on clinical features, and then move on to those that may be less likely but that the patient could still fit into. Unfortunately, this is the best way we have with the present technology. The only exception is subtelomere FISH, which is a test that can look at the tops and bottoms of all the chromosomes in one test. You can ask your doctor if he has ordered this test or if he thinks it is worthwhile to perform based on your child's features. Amy Curry CDO Medical Advisor


Q: FISH: Our doctor is fishing our only certain chromosomes-one at a time? Isnt there some way to check all the chromosomes at once?

FISH is a very specific procedure where DNA probes are used to detect whether or not a specific piece of DNA on a chromosome is present or not. With our current technology, you can only FISH for one deletion at a time. Geneticists will start out with a deletion that is most likely based on clinical features, and then move on to those that may be less likely but that the patient could still fit into. Unfortunately, this is the best way we have with the present technology. The only exception is subtelomere FISH, which is a test that can look at the tops and bottoms of all the chromosomes in one test. You can ask your doctor if he has ordered this test or if he thinks it is worthwhile to perform based on your childs features. Amy Curry CDO Medical Advisor

 


Q: Food allergies, weight gain and chromosome deletions?

Food allergies are very complex. It has been our experience that many children with chromosome variations have food intolerances/allergies. The difference between an allergy and an intolerance is that allergies are a specific reaction to a substance mediated by the immune system. An intolerance is just a reaction that can occur for a variety of reasons and is a food that is not tolerated or absorbed or whatever. Having said that, some children with chromosomal variations have food allergies/intolerances at what seem to us a high rate. The reasons are not clear why. It may be that there are some stresses on the immune system that cause this reaction. There may be GI tract issues that occur at a higher rate.

Weight gain is also a significant issue for many children with chromosomal variations. This may be due to inadequate intake as some children have difficulty with feeding. It also may be due to an increased metabolic need. Some disabled children have muscle contractions or other issues that use up a huge amount of calories that can be unnoticed. Looking at the diet with a dietician and maximizing strategies to increase calories is important. This is a setting of food allergies/intolerances can be a challenge. A skilled dietician can be invaluable to look at this in the individual child. This is a very general answer, but there are so many variables.

Robert Wallerstein MD


Q: Food allergy testing.

This is a good question that is answered differently by different allergists.
There is blood work looking at antibodies for any foods in question and
also skin testing where a small amount of the food in question is placed
in the skin with a tiny needle to look for a reaction. Different allergists
feel differently about which is best. It depends a lot on the specific
situation. An allergist or pediatrician can order the blood work available
at most commercial laboratories. The skin testing is usually done by an
allergist. In our practice, we have done the blood work and it is effective.

Robert Wallerstein MD
Donna Wallerstein
Certified Genetic Counselor


Q: For many years I assumed I had Klinefelter Syndrome (47XXY). Recently I had some general testing done which seemed to indicate I have a rare case of 47XXY with female phenotype due to a SRY mutation. Please tell me what is SRY and what does it mean?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

The SRY is a gene located on the short arm of Y-chromosome. This gene is necessary to produce the development of testicles. If this gene is mutated or missing the person will have basic female genitalia.

 

There are several reports in the literature of XXY patients who also had deletions of the SRY gene (or mutations of this gene). But as far as I know all of these patients had a female phenotype. Your correspondence indicates that you identify as a male and that makes a deletion of the SRY gene doubtful. Furthermore, a reliable genetic diagnosis requires specific laboratory examination.

CDO¹s library contains several articles discussing 47XXY, the SRY gene and individuals with abnormal SRY.  For more information on any library
article, please contact info@chromodisorder.org

 


Q: For unknown additional genetic material - is there a way to determine its origin?

Yes, there is a way to determine the origin of this genetic material. Many cytogenetics labs will use a technique called SKY (spectral karyotyping) that will essentially paint all the chromosomes a different color. The extra piece on this chromosome should be painted some color, and then the lab may be able to determine what chromosome it is from.

Amy Curry Sturm
Certified Genetic Counselor
CDO Medical Advisor

Q: Frequency of chromosome disorders.

Down syndrome (Trisomy 21): The birth prevalence of trisomy 21 is ~1/650 births.
Patau syndrome (Trisomy 13): The birth prevalence for free trisomy 13 is ~1/12,000. Edwards syndrome (Trisomy 18): The prevalence is ~1/5000 to 1/7000.
del(4p) syndrome (Wolf-Hirschhorn syndrome): The prevalence is ~1/50,000 births. Turner syndrome: The prevalence is ~1/2500 female births. Klinefelter syndrome and its variants: The prevalence is ~1/1000 births.

Amy Sturm
Certified Genetic Counselor

Q: Gardner Syndrome & balanced translocation involving 5q.

Gardner syndrome occurs due to a change in a gene called APC. The APC gene is located on the long arm of chromosome 5 between bands q21 and q22. (The "bands" refer to defined staining patterns.) The translocation you describe involves a break on chromosome 5 at band q23.2, which is very close to q21 and q22. It may be unrelated, but it seems very close to be coincidental, and I would wonder about it.
Perhaps the break does involve the gene somehow, or perhaps the break affects the function of the gene because it is nearby. Testing of the APC gene can be done. Follow-up with your geneticist is recommended.

Karen Heller
Certified Genetic Counselor

Q: Give more detail for 45X/46XY.

It is sometimes hard to predict the clinical outcome of mosaic conditions, as one cannot predict the percentage of normal vs. abnormal cells from organ to organ. In general, many 45,X/46,XY individuals are normal-appearing males, and are reared as such. However, given the presence of a 45,X cell line, the health care provider should do a full evaluation looking for different things that can go along with Turner syndrome (an echocardiogram to look for heart defects, renal/kidney ultrasound, etc.).

Most individuals with Turner syndrome have normal intelligence. However, learning disabilities are seen more often, particularly with regard to spatial perception, visual-motor integration, mathematics, memory, and attention span. From the email below, it sounds like your patient is only slightly delayed, as he is 2 years old and functioning at a 22-month level. Hopefully, his evaluation looked at verbal and nonverbal functioning (the nonverbal IQ's in Turner syndrome tend to be lower than verbal IQ).

I would presume that the risk for gonadoblastoma is there, just given his karyotype. However, I did find an article that mentioned that the risk is greater when the testes are located intra-abdominally. Whether his risk is lower, given that his testes are descended, I do not know. I would recommend that they see a urologist to discuss this, as well as an endocrinologist to discuss growth hormone therapy. I have included a recent abstract addressing this issue - not sure if he has short stature or not. An endocrinologist could better address any potential complications.

Short stature in children with an apparently normal male phenotype can be caused by 45,X/46,XY mosaicism and is susceptible to growth hormone treatment.

Richter-Unruh A, Knauer-Fischer S, Kaspers S, Albrecht B, Gillessen-Kaesbach G, Hauffa BP.

Department of Haematology/Oncology and Endocrinology, University Children's Hospital, Hufelandstrasse 55, 45122 Essen, Germany.

Girls with unexplained short stature are routinely screened for the presence of Ullrich-Turner syndrome by clinical examination, laboratory tests, and karyotyping. In this study, we performed chromosomal analysis in boys to explore the role of 45,X/46,XY mosaicism for short stature in males. Short-term effects of growth hormone treatment in male 45,X/46,XY individuals were compared retrospectively to those in female patients. We report six boys with a normal-appearing male phenotype and 45,X/46,XY mosaicism, four of whom were diagnosed postnatally because of short stature. Two boys were diagnosed prenatally by amniocentesis. Five boys were short and were treated with growth hormone (0.04-0.05 mg/kg per
day) in analogy to girls with Ullrich-Turner syndrome and gonadal dysgenesis. With the exception of one patient in whom treatment was initiated only at the age of 14.6 years, the male patients with 45,X/46,XY mosaicism responded to short-term growth hormone treatment similarly to females with an increasing height SDS. CONCLUSION: 45,X/46,XY mosaicism remains undetected in some short boys because this group is not routinely karyotyped. We recommend chromosomal analysis of boys with otherwise unexplained short stature who are short for their families. Growth hormone treatment should be offered to short boys with 45,X/46,XY mosaicism and a predicted adult height below the mid-parental range within clinical trials.

Hope all of this helps.

Michelle Springer Certified Genetic Counselor

Q: Growth chart for children with chromosome abnormalities?

There are growth charts for individuals with specific chromosomal disorders such as Turner syndrome and Down syndrome. These charts are created by compiling growth records from many hundreds of individuals. A large number is needed for the average growth to be statistically significant.

For children with other chromosomal disorders, the issue is that it is difficult to compile the numbers of growth measurements for each specific chromosomal disorder. Each specific chromosomal deletion has differences in growth and therefore, should be considered separately. So, the idea of a growth chart is not impossible, but is more difficult for the rarer deletions.

Robert Wallerstein
Medical Geneticist

Donna Wallerstein
Certified Genetic Counselor

Q: HBO Therapy - does it help?

Hyperbaric oxygen therapy is used conventionally for patients with carbon monoxide poisoning and burn victims. In these cases, the increased oxygen is thought to help replace the carbon monoxide in the blood system and to increase healing of burns. The mechanisms are straight forward.

Hyperbaric oxygen therapy is being thought about as an alternative therapy in other situations such as developmental delay. The mechanism in this case is not so straight forward. The suggestion may be that increased oxygen would stimulate areas of the brain. The benefit is not clearly understood. In the conventional medical literature, there are no studies that support its use in non-standard situations. We simply have no information to base a judgement. It does not sound harmful to me and a family would have to weigh the limitations of the therapy with ability of the child to tolerate it, cost, and availability as factors. There are areas of medicine that we simply do not have enough information to make a solid recommendation either for or against.

Robert Wallerstein MD

Q: Hearing loss & rare chromosome disorders

In children with chromosome issues, there can be many forms of hearing loss. As you likely know, there are 2 main forms of hearing loss: conductive ( mechanical deafnes) and sensorineural (nerve deafness). Children with chromosome isses can have either one. The deletion or duplication of chromosomal material can cause differences in the shape of the ear inner and outer and predispose to hearing loss. The chromosome issue can also predispose to differences in the nerves of the ear causing hearing loss.
This is not necessarily a part of each chromosomal disorder, but chromosome problems do create increased risk for hearing loss. Therefore, it is our clinical practice to recommend hearing screening as a part of the management of children with chromosomal problems. This recommendation should be broadened to all children with developmental issues as hearing loss can be a major cause of speech delay and is treatable if detected. Any concern about hearing should be discussed the child's health care provider and appropriate testing arranged.
Extreme sensitivity to sound is a part of sensory overload where a child has difficulty screening out multiple stimuli from the environment. When you are in a noisy room, you have to focus on a small number of sounds or you will get overwhelmed and loose the ability to function in that setting. For many of us, this is a skill that we take for granted. Many children with chromosomal or other developmental issues have difficulty with focus and discriminating between sounds and get easily overwhelmed. This is a different mechanism from the hearing loss, but is also associated with chromosomal issues, but is common with other developmental conditions as well.
Robert Wallerstein MD
Medical Geneticist
CDO Medical Advisor


Q: Heterochromatic inversions?

Inversions having breakpoints within the heterochromatic (centromeric) regions of chromosomes 1, 9, 16, and Y are frequently seen and are to be thought of as variants, not abnormal chromosomes. No genetic risks are known to be associated with these inversion variants.

Q: Hi my son was diagnosed with a 20 p 12.1 deletion that affects the Gene MacroD2. I read in the internet that there are discussions about autistic symtoms (which he has) connected to this gene. Could you tell me more about it? Thank you!

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 



Answer:

 

 

The gene MACROD2 is a very large gene (more than 2 Mb) on chromosome 20p12.1. The function of the protein coding by this gene is not very clear, but there is no doubt that both mutations and deletions of this gene can lead to autism. The association of MACROD2 with autism has been confirmed in several studies.  CDO has several scientific articles about this issue available in our library.  To access these or any library article, simply register with CDO and request an information packet. 

 

Information is also available in Spanish and Portuguese


Q: How common is it that children with chromosome disorders go undiagnosed?

This situation relates to the earlier question as it is a scenario where the microarray technology can be helpful to look for a microdeletion not initially detected. I will say that in clinical practice, we have seen many children where we feel very likley that there is a chromosome problem and all testing is normal. This may represent a single gene issue not detectable on chromosome analysis. This situation is one where the clinical skill ofthe geneticist is important in assessing whether a known genetic syndrome is present or other possibilities. It is a common scenario.
Robert Wallerstein MD
Medical Geneticist


Q: How long does a chromosome test take?

A typical chromosome analysis usually takes anywhere from 2-3 weeks at most centers. If there is a complex rearrangement in a family, though, it may take longer, because much more complex studies need to be performed. Usually, however, I would not anticipate it taking longer than 1 month.

Amy Curry
Certified Genetic Counselor

 


Q: I am searching for a particular syndrome.

You might find this website helpful.

http://www.whonamedit.com

Q: I was informed recently that I am a carrier of chromosome 1q21.1 duplication, researching information on my own I discovered links to intellectual disability and autism – would you please explain how this would relate to any future pregnancy?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

 

Answer:

The clinical significance of small proximal duplications of chromosome 1q21.1 is not very clear.  Yes, several patients with such duplications were found among patients with epilepsy, autism or psychomotor retardation. But it does not mean that dup 1q21.1 was RESPONSIBLE for all these abnormalities.

 

But what happens in real practice?  Scientist A studies patients with (for example) autism. Assume that he studied 200 kids and found two having this duplication. Scientist B studies patients with epilepsy and finds one with dup 1q21.1.  Scientist C examined 150 patients with heart defects and reported two with dup 1q21.1.  Assume that genetic counselor has a consultation with a woman whose prenatal test showed this duplication in the apparently normal fetus. This counselor checks the medical literature and finds that there are 5 reports on this duplication, and in 3 cases the patients had some mental issues.  What can he/she recommend? Of course, it is an oversimplification, but you can see my point.

 

There is another kind of study reported in the literature when representatives of a large laboratory analyze all persons with any give abnormality found in their center. They may report 10 or 15 patients with dup 1q21.1 (or any other microduplication), and all (or vast majority) of these persons had some mental or physical problems. But these problems were an indication for cytogenetic examination, and the discovery of any microduplication does not guarantee its etiological significance.  I do not want to say that dup 1q21.1 is harmless in all cases, I just want to say that we do not have any real information to make a conclusion about its significance.

 

If we could find a large number (200-300) of newborns with dup 1q21.1 (or any other microduplication) and follow these children for 10-15 years we could then see how many will eventually experience symptoms or deficits and how many will remain healthy.

 

In my opinion the cytogenetic examination of both parents is a prerequisite for any decision about a pregnancy in all cases where a microduplication 1q21.1 (proximal or distal) is found in a fetus. And if one of the healthy parents is a carrier we have a very good chances to believe that the baby will be healthy. 

 

Attached is the article by Rosenfeld et al. – the largest publication on proximal dup 1q21.1. There are many other single cases, but in all these cases the authors report results of a cytogenetic examination in the specific groups of patients.  One studies heart defects and reports this duplication among persons with heart defects. Another studies schizophrenia and reports several patients with dup 1q21.1 in his study group. So, these results are inconclusive regarding the real significance of dup 1q21.1.

 

Even in families with much larger duplications of 1q21.1 the clinical manifestations in different members of the family may be very different.

 

Just today I read another article where a son of a woman with another microduplication (16p11) had some abnormalities. He had the same microduplication as his healthy mother.  But his doctors decided to examine his genome. They found mutations in another gene, which was really responsible for child’s disorder. Without these tests this child would be considered as having his disease due to duplication. 

 

Until now we do not have any real information about the significance of proximal dup 1q21.1, but in my opinion the transmission of this duplication from the healthy parent to the fetus should not be considered as an absolute indication for termination.

 

Best wishes

 

 

Iosif Lurie, M.D., Ph.D.

 
Editor’s Note:  The CDO Library contains many new articles on this microduplication.  All articles are free to CDO Members.  Please email info@chromodisorder.org for details. 

Q: I would like to know about Pierre Robin Syndrome or Sequence and what are the chances for a person who has it to give birth to a child with the same syndrome. My daughter has isolated PRS and no other member of our family has it. Her DNA tests showed that she doesn't have any gene disorder.

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 



Answer:

 

If a patient has isolated Pierre Robin sequence and there are no other

similarly affected persons in his/her family, the risk for siblings of the

patient is less than 1%. Risk for the offspring of the affected person

(for the children of your daughter) is approximately 2-3%, because we

 

cannot exclude a new dominant mutation.


Q: I'd like to know more about De Novo balanced translocation.

In general, this balanced chromosome translocation is very unlikely to have any effects on development or health of the individual who has it. Approximately 1 in 500 people in the general population has a balanced translocation. It is possible to predict, with about 95% certainty, that balanced translocations will be benign. What parents may worry about is the rare case in which apparently balanced translocations actually disrupt an important gene, with consequences to the baby.
In your particular case, the most important information will come from detailed ultrasound examinations, at least until the baby is born, when an even more reliable physical assessment will be done by your pediatrician. Although a balanced translocation (from a statistical point of view) really should not be cause for alarm, it is cause for enhanced ultrasound surveillance during pregnancy, and the pediatrician should know about it so that a careful examination can be done for additional reassurance.
When your baby is grown and old enough to consider starting his own family, he must be directed to seek a consultation with a geneticist. This is a long time away, but you need to know about it. He can have children with normal chromosomes, or children with a balanced translocation like his. However, there is also a risk that he could have a child with an unbalanced chromosome rearrangement, which would likely have severe consequences. Not to worry too much, however, because we already have advanced methods of diagnosing chromosomal disorders early in pregnancy (such as CVS or amnio) and also have pre-implantation diagnosis (in which the baby is conceived in a "test-tube" and testing can be done prior to implanting the embryo in the uterus). This type of testing will presumably be even more refined and widely available by the time your son is grown and is ready to think about such things.
You should certainly have input from a clinical geneticist (physician certified to counsel individuals about a wide range of genetic conditions) your doctor may even be a geneticist, but I don't have that information and wanted to make it clear that your baby's chromosome finding deserves input from a specialist in genetics. The particular chromosome rearrangement has been detected before (Liberfarb RM, Atkins L, Holmes LB. A clinical syndrome associated with 5p duplication and 9p deletion. Ann Genet. 1980;23(1):26-30.
PMID: 6965836). Carriers were not affected but children with unbalanced translocations had significant medical issues. Sincerely, Thomas Morgan, MD


Q: Incidence of inversions in the general population.

Inversions are fairly common. Approximately 1 in 500 people has a chromosome variation of some kind. Inversions are in that statistic.

Donna Wallerstein
Certified Genetic Counselor

Q: Inherited Chromosome Deletions.

A person with a deletion can pass it on to their offspring. Since your son has two number 10 chromosomes, one that is normal and one that has the deletion, it is a 50/50 chance that he will pass on the deleted chromosome to a child and a 50/50 chance that he will pass on the normal, non-deleted chromosome to a child. I think it would be a very good idea for your son to see a genetic counselor, so now that he is at an age where sex and reproduction is something he may start to think about, he can have and be aware of this information. Since I don't know the extent of your son's chromosome abnormality, I do not know if he has the capacity to care for and raise a child. However, if he does, then he has many different options available to him. If your son does have a pregnancy with a partner, there are options for prenatal diagnosis including chorionic villus sampling in the 1st trimester of pregnancy and amniocentesis in the 2nd trimester of pregnancy that can let he and his partner know whether or not the baby inherited the chromosome deletion. There is also a technique called preimplantation genetic diagnosis (PGD) where fertilized eggs can be tested before they are implanted into a woman's uterus to see if they have inherited the chromosome abnormality or not. This involves in vitro fertilization and is quite costly. Your son would also have the option to adopt children if he did not want to have biological children.

Amy Sturm
Certified Genetic Counselor

Q: Inquiry on genetic tests.

The karyotype is the analysis of the chromosomes under a microscope.
The karyotype will detect if the correct number of chromosomes is present and also whether there are any pieces of chromosomes that are missing, duplicated or rearranged. An abnormal number of chromosomes or any "imbalance", that is, extra or missing chromosomal material, is likely to cause problems such as birth defects, developmental delay and mental retardation.

A "high resolution" karyotype, like a high resolution photograph, has good clarity, but it still would not pick up a change in a very small piece of chromosome that is below the level of resolution of the microscope, and it will not pick up changes with individual genes.

Comparative genomic hybridization (CGH) or microarray analysis is able to analyze the chromosomes in more detail, by checking for the presence or absence of very small pieces of chromosome material all along each of the chromosomes. So, sometimes, CGH will pick up a tiny deletion or duplication that a karyotype will not. "FISH" is similar to CGH, except that a FISH test is targeted to a particular spot on a chromosome. At this time, the use of CGH is limited to certain circumstances, because researchers are still learning how to interpret many of the findings.

In order to test individual genes, the doctor has to determine which gene he/she suspects is causing a problem, and then find a lab that is able to test the sequence of that particular gene. There isn't a test that will scan all of the genes looking for one that has a problem.
Karen Heller Certified Genetic Counselor


Q: inv(2)(q21q23)

Inversions are considered to be benign polymorphisms in most cases. The inversion you describe is paracentric inversion meaning that it does not involve the centromere and involves the long arm of chromosome 2. These inversions in MOST cases are considered to be harmless and will not cause any abnormality in the individual. But each inversion is unique based on the breakpoints and a risk for any abnormality in the individual carrying the inversion will depend on many factors mainly: 1) if the inversion which is apparently balanced by classical cytogenetics is really balanced, there are several examples in literature indicating that these so called balanced rearrangements are in small proportion of cases are in fact unbalanced; 2) If any of the breakpoints disrupt a gene of important function. The way to figure these two scenarios are as follows: 1) To see if the inversion is really balanced, one can investigate copy number changes by microarray CGH analysis (offered by Baylor and a company called Signature genomics which will cost approximately $1000; call them to check the recent cost);
2) to check if the breakpoints disrupt a gene is an academic question at this point, there are several experts working on this purely for research with the aim that one day this information will help in better understanding to these chromosomal rearrangements. These researchers are interested in dissecting out the gene disruption causing the ABNORMALITY in the individual carrying the chromosomal abnormality.
One such group is at Harvard medical school called as DGAP (developmental genome anatomy project), of which I was an active researcher till June of last year.
Of note is that the individual carrying a paracentric inversion may have difficulties in having kids due to unbalanced gametes formed.
Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics


Q: Inv(9) (p12q13) & simian creases?

Your child's pericentric inversion 9 certainly could be a benign variant, and that is likely. As doctors have told you, it is not necessarily abnormal to observe a pericentric inversion of chromosome 9. Bilateral "simian creases" (i.e., creases across the palms) do not raise my level of suspicion significantly. However, as you are correct to assume, not all chromosome 9 inversions can be confidently deemed "normal" beyond any possible doubt. We usually don't know, with each particular child, exactly where the inversion occurred, and whether or not a gene or other important stretch of DNA could be impacted negatively. Usually it's not, but parents understandably want to know "for sure" that everything's OK.
In your situation, I think that a cautious approach to monitoring your child's developmental progress is warranted. If everything goes according to schedule, then I wouldn't worry. However, as a general rule, any person with a chromosomal inversion should know, when he or she is old enough to consider having children, that genetic counseling is indicated. You don't have to worry about this for a long time, but I do recommend that your child visit a geneticist when he or she turns 18 (or sooner in the extremely unlikely event that he or she would have children before age 18). Please let me know if you have any questions, and certainly contact me if there are any concerns about his or her development. Sincerely Yours, Thomas Morgan, MD Yale University

Q: Inversion and testing for missing genetic material.

A careful chromosome study by visually looking at the banding pattern tries to determine if any of the bands are absent or disrupted. Remember that each chromosomal band contains about 200 genes or so. If a whole band is missing, that can lead to some significant disruption.
If some cases, molecular probes are used, it depends on the particular inversion and which areas are involved.

Donna Wallerstein
Certified Genetic Counselor

Q: Inversion symptoms.

An inversion is a chromosomal rearrangement where a piece of chromosomal material is flipped over. The points where the piece flips can be disrupted and if there is a critical gene in that area it can cause developmental problems.
Many inversions are completely asymptomatic and individuals do not know that they carry an inversion. There are some inversions so common that they are considered normal variants. Other inversions can be more problematic. They can cause developmental problems in a child or can be related to pregnancy loss or birth of a child with chromosomal problems.

Donna Wallerstein
Certified Genetic Counselor

Q: Inversion: I'm looking for additional information on miscarriage percentages and possible birth defects if one parent carries this inversion.

This is a normal variant, well-known in the population, particularly among individuals of Ashkenazi (Eastern European) Jewish ancestry. It is very unlikely that this would be associated with any increased risk of miscarriage. We would read this as a normal result. 

Donna Wallerstein, MS 
Certified Genetic Counselor 


Q: Inverted duplication of X chromosome.

I can tell you that what you have is a complex rearrangement of one X chromosome that results in having an extra copy of a piece. It is not clear from the karyotype whether there is anything missing as well. What does this mean for you as a person? Rearrangements like this are unique. From what we know from persons with similar (not identical) rearrangements, you are likely to experience premature ovarian failure. There could also be effects on height. Otherwise we do not know of any other consequences of this type of disorder. The frequency of similar rearrangements of the X is probably less than 1 in 10,000. The best name for it would be "inverted duplication of X." It sounds like you are being treated for ovarian failure, which may well have contributed to osteoporosis. Questions about symptoms and drug dosages must be addressed by your physician, preferably an endocrinologist.

Andrew Zinn MD
Medical Geneticist

Q: Is a large deletion (5 q 15-23) (107 genes - 20.3 Mb) compatible with life? If yes, what is the life expectancy?

Answered by Dr. Iosif Lurie, Medical Geneticist, CDO Medical Advisor

 

Yes, this deletion is compatible with life.  There are several reports of patients having deletions of a similar size in 5q15q23. Children may have agenesis of the corpus callosum, cleft palate, and kidney defects (horseshoe kidney). Hearing defects were found in several patients with this deletion.  Moreover, this area includes the APC gene - absence of this gene causes multiple colorectal polyposis and malignant tumors of the colon.


Q: Is it possible to determine from which parent the gene for the deletion came from?

Yes, in theory, and only on a research basis, but it would not have any clinical use, and can have negative psychological consequences, so it is not recommended. It is important to know that chromosomal deletions are random events that can happen to any parents. The occurrence of a deletion is not related to anything that either parent has done.

Thomas Morgan MD
CDO Medical Geneticist

Q: Is there a link in 5p- and slow weight gain and skulls with sutures that have closed too early?

Slow growth is seen in 100% of 5p-. There does not appear to be a relationship between 5p- and premature closure of the sutures, or craniosynostosis. I could only find one report of the two conditions co-occurring, and it was in the setting of a complex chromosomal rearrangement that included trisomy 13q as well as 5p-. It would be useful to know what types of investigations were done to determine the nature of the chromosome abnormality, and consider doing FISH studies to verify that it is a simple deletion of 5p.

Dr. Andrew Zinn
Medical Geneticist
CDO Medical Advisor


Q: Is there a risk of second child with chromosome abnormality?

This estimate would depend on the actual chromosome abnormality. The most common chromosome problems trisomies (where there is an entire extra copy of a chromosome) is usually caused by an accident of cell division and therefore is not thought to be recurrent in the majority of cases. There are some rare families with situations such as a trisomy or other condition where a seemingly sporadic chromosome abnormality can recur. The 1% is used to include these families, however the actual risk to most families is considerably less, to some it is higher. The problem is that it may not be possible to pick out the families with the higher risk so the 1% is used. The mechanism where families can be at higher risk may be gonadal mosaicism. This is a term to indicate individuals who have cells in their gonads (ovaries or testicles) with different chromosome constitutions that predispose to chromosome abnormalities. These individuals are normal in other ways and are not able to be distinguished. It might be possible to look directly at cells from the gonads from a biopsy-but who wants that. This is not done on a clinical basis. This is also quite uncommon. So the short answer is that 1% does apply to many situations and may be correct. If we were to know the chromosome abnormality involved it would be possible to comment further.

Robert Wallerstein MD


Q: Is there any evidence that 8p deletion kids have higher cholesterol, triglycerides,etc?

I looked at the literature. There are some reports of linkage based studies which suggest a possibility of a locus involved in cholesterol metabolism. But these studies have not been replicated and a definitive answer is lacking. So at this point, it is not known whether aberrations of this genomic region would be responsible to affect cholesterol levels.

Shashikant Kulkarni
Director of Clinical and Molecular Cytogenetics
Assistant Professor of Pediatrics
Genetics & Genomic Medicine
Department of Pediatrics


Q: Is there support for XYY?

The only group I am aware of that deals with XYY is Klinefelter
Syndrome and Associates, http://www.genetic.org/
In fact, they are holding a Trisomy X and XYY Conference in March.

Andrew Zinn MD

Q: Isochromosome and Isodicentric chromosome, is there a difference?

Yes, Isochromosome has one centromere with 2 short or long arms attached. Isodicentric has two centromeres and a short segment in between, in addition to the long and short arms.
Andrew Zinn Medical Geneticist
CDO Medical Advisor


Q: IVF & chromosome abnormality?

The IVF process has been studied extensively. For those of you unfamiliar, it is the process whereby fertilization is performed in the laboratory and embryos are implanted back into the uterus for pregnancy. There really is no increased risk of chromosome abnormalities or other birth defects to babies born after this manner of conception. This does not take into consideration the possibility that the parents may be experiencing infertility for reasons that are genetic and therefore may be at a higher risk for certain problems unrelated to IVF. However, all things being equal there are no increased risks of problems after IVF.

Robert Wallerstein MD


Q: IVF & Triploidy?

As you probably know, triploidy means that there were 69 chromosomes
instead of the typical 46 chromosomes. Most often, this is caused by a
single egg being fertilized by two sperm. Therefore, there are often
two paternal sets of chromosomes, and only one maternal set. However, in
your case, this is very unlikely to be the case because ICSI was used to
fertilize the egg with a single sperm. However, triploidy can also be
caused by the "duplication" of the maternal genetic material early on in
the development of the egg or embryo. This is more likely to be the
cause of the triploidy in your case.

Although ICSI is a relatively new procedure, there are no definite
reports of ICSI consistently causing any type of chromosomal
abnormalities. As far as I know, I have heard of no known reports of
ICSI causing triploidy. ICSI can increase the fertilization rate, but
it can not prevent chromosomal abnormalities from occurring in a
pregnancy. Although ICSI can nearly eliminate all risk of triploidy
associated with dispermy (two sperm fertilizing one egg), it can not
prevent other mechanisms of triploidy. Therefore, it is impossible to
know what caused the triploidy in your pregnancy, but it is very
unlikely that ICSI was the cause.

Some labs have the technology to be able to tell which parent
contributes an extra chromosome, or in the case of triploidy, a whole
extra set of 23 chromosomes. However, I am unsure whether many
laboratories would agree to use this technology for this purpose
because, in most situations, it makes no difference which parent
contributed the extra set of chromosomes. There is usually no change in
recurrence risk (the chance that triploidy would happen in another
pregnancy). The recurrence risk for triploidy is about 1%. In other
words, there is about a 1% chance for you to have another pregnancy with
triploidy, regardless of whether the extra set of chromosomes came from
the mother or the father (depending on your age, there may be an
increased risk for you to have a pregnancy with extra or missing
chromosomes, such as those that result in Down syndrome). That is why
many labs might not offer testing in this situation; because the risk
for the next pregnancy does not change, and testing will only lead to
increase undue and unnecessary "blame" for one person in the couple.
Michael Graf CDO Medical Advisor Certified Genetic Counselor

Q: IVF with ICSI - increased risk of triploidy or sex chromosome abnormalities?

The Reproductive Genetics Institute said the risk they inform patients about with ICSI is a 0.8% risk for sex chromosome abnormalities. Just based on having the ICSI procedure, there is not an increased risk for triploidy. Triploidy in this case would occur by starting off with a diploid sperm or egg.

Amy Curry Sturm Certified Genetic Counselor

Q: Klinefelter Syndrome - 49XXXXY. Please explain.

"49, XXXXY Syndrome." This variant of Klinefelter Syndrome is caused by the inheritance of three extra X chromosomes. Having additional X chromosomes, in general, leads to more prominent manifestations of
Klinefelter Syndrome. There may be a distinctive facial appearance. There is
much to know about the specialized medical care of children and adults with Klinefelter Syndrome, and all children with this diagnosis should be under the care of an endocrinologist, a primary physician, and a clinical geneticist (at least for the diagnosis and counseling).
However, some of the key issues for parents to know about are as follows:
(1) Extra X chromosomes impair testicular development in males, usually leading to infertility. Lack of testicular development makes it necessary to treat boys with Klinefelter Syndrome and its variants with testosterone.
(2) Low testosterone puts boys at risk for osteoporosis, and your son's doctors will assess his bone mineral density, bone health, and risk for fractures.
(3) Developmental delay is more likely in boys with higher numbers of X chromosomes, and a developmental assessment should be routine.
(4) An echocardiogram (ultrasound of the heart) should be done to check the function of the mitral valve (which prevents blood from flowing in the wrong direction when the heart pumps).
(5) Breast tissue can develop in boys with Klinefelter and its variants, sometimes requiring surgery, but always needing routine surveillance for breast cancer.
(6) Varicose veins can occur.
The above list is partial, only to give a sense of the specialized medical care that all children with Klinefelter and its variants should have. Your doctors will be able to provide you with information that is more specifically tailored to your son. "KS & Associates," in addition to CDO, is a support organization for parents of children with Klinefelter Syndrome and its variants. There is also a listserv for parents of children with 49, XXXXY (http://klinefeltersyndrome.org/49er.htm). I hope this information will be of some help to you. Sincerely, Thomas Morgan, MD Dept. of Genetics Yale University

Q: Life Expectancy: What is the life expectancy of those with chromosomal disorders?

The question that you raise is an important one that does not have a
clear answer. The life expectancy for people with chromsomal deletion
syndromes is usually related to the manifestations of the chromsomal
condition. As your genetciist said that the shortened life span is
related to clefts and poor nutrition. The basic answer is that the
chromosomal deletion can cause other medical issues such as a cleft or
a heart defect. A heart defect can be life threatening. If a person has
a serious heart condtion, this can shorten his or her life. This can be
related to the chromosomal issue and in that sense the chromosomal
condition can shorten the lifespan. Since chromosomal variation are so
different in the physical ways in which they manifest, this is a wide
open question.

Another issue in the answer to your question relates to the care of
individuals with developmental disabilities. Many years ago surgery was
not routinely offered to individuals with chromosomal syndromes to
repair certain anatomic defects. These individuals suffered from the
effects of physical differences caused by their chromosomal variations.
The medical issues of a heart defect not repaired or a cleft not
repaired are significant. I care for an adult woman who has a cleft
that was not repaired. She has speech and respiratory issues that would
have been prevented of the cleft was repaired in infancy. The consensus
in the medical community has changed and quality of life issues are an
important issue to consider in making decisions about care. So
individuals today who have the same chromosomal condition, but who
receive more aggressive medical care may have better long term
outcomes.

This also speaks to the information that is available about different
chromosomal issues. The natural history studies of different
chromosomal conditions were often done many years ago and are not
tracking those people who had increased medical care. The old studies
may not apply to children treated in the 21st century with improved
techniques. Also, chromosomal condition are not common so collecting a
large series of individuals is not easy. It takes a large number of
patients to get enough information to make generalizations about a
condition. These numbers are just not always available.

So, there are many questions unanswered. It continues to remain
important to chart each child's course as an individual looking at his
or her issues as a unique condition.
Robert Wallerstein MD
Medical Geneticist


Q: Limited FISH test.

If I understand your question correctly, you are asking why, given an ultrasound finding of increased nuchal translucency, doctors might choose to order a test that can only detect an extra chromosome 21 (Down Syndrome), 18 (Edwards Syndrome), 13 (Patau Syndrome), X, or Y, when a more comprehensive test could detect many more genetic syndromes. Although I can't comment on your sister's particular case, not knowing all the details of her ultrasound findings, discussions with her physicians, etc., I can provide you with some information about the current state of prenatal testing.
The local standard of medical care does not necessarily change the moment a new test is developed; it gradually diffuses into the practice of medicine. In any given locality, there may be a "standard procedure" to rule out Down Syndrome (which is by far the most likely diagnosis), when increased nuchal translucency (an ultrasound view of the back of the unborn baby's neck) is found. Additional testing may not be standard in all medical centers.
However, genetic testing is evolving so rapidly that many medical systems simply can't keep pace. By medical systems I mean more than just doctors, who must operate within the complex and often frustrating context of insurance regulations, office systems, laboratory systems, and hospital systems. I believe that expectant parents, and parents of children with developmental issues, will continue to press for more comprehensive genetic testing options, and insurance companies are quite concerned about this trend, due to the high cost.
Patients rightly want their doctors to always be at the cutting edge of every new technology, and want to be fully informed about all possible options so that they can choose from among them, even if the local medical system has not yet absorbed an innovation. This drives physicians to specialize in order to keep up with advances. The medical speciality of Clinical Genetics arose in this context. In general, patients or parents of children with known or suspected genetic diagnoses can expect to get the most up-to-date information about the latest genetic testing options from a physician who is board-certified in Clinical Genetics, or from a genetic counselor who works with a clinical geneticist or independently. I would recommend that any patient or parent facing a possible genetic issue seek genetic counseling from a clinical geneticist or genetic counselor and be sure that the doctor you choose is willing to take a sincere interest in your case and answer any questions that you might have. Thomas Morgan, MD Department of Genetics/Yale Child Study Center Yale University

Q: Long Term Effects of Inversions.

If the inversion is related to the developmental issues, the developmental issues are likely to be long term. It would be important to understand if other people in the family appear to have the same inversion. If other unaffected people carry the same inversion, then it is not likely related to the developmental problems.

Donna Wallerstein
Certified Genetic Counselor

Q: Marijuana use and chromosome disorders

Marijuana use is not known to affect the chromosomes of a baby. However, some studies suggest that marijuana use can decrease the likelihood of a couple becoming pregnant (perhaps due to decreased sperm count) and some studies suggest marijuana use during pregnancy can cause slower growth of the unborn baby and/or increased miscarriages. Other studies have not confirmed these findings. While there are limited long-terms studies of children who have been exposed to marijuana during pregnancy, some of these studies suggest that these children may have subtle differences in their ability to pay attention while other studies have not found this to be true. Although marijuana use has not definitively been linked with any specific birth abnormality or learning disability, it is suggested that parents should refrain from marijuana use during pregnancy and around children to minimize any potential risks. If an exposure has occurred, your physician and/or genetic counselor can more accurately describe any potential risks.

Michael Graf
Certified Genetic Counselor


Q: Marker chromosome - prenatal diagnosis.

Your doctors are taking appropriate steps to further characterize the marker.  If it is inherited from a developmentally normal parent, then a marker is predicted also to have no consequences for the child.  If it is not present in either parent, then it is very difficult in most cases for doctors to predict what consequences, if any, the marker will have.  The range of outcomes is broad, ranging from entirely normal development to serious concerns, unfortunately, meaning that a marker can sometimes result in developmental delay and physical developmental abnormalities.  However, potentially positive signs include a small sized marker (as you reported), and one that is mostly heterochromatic (meaning darkly stained, indicating a relative lack of genes), or a marker that can be definitely identified and which has been reported before in normally developing children.  Ultimately, detailed ultrasound, careful examination at birth, and close monitoring of cognitive and motor development are required for reassura