Inherited Microdeletions or microduplications – a benign finding?

15q13.3 microdeletion

Are inherited microdeletions or microduplications a benign finding or more complex?

Small deletions or duplications of chromosomal material may be found upon examination of patients with several neurodevelopmental problems (autism, epilepsy, intellectual disability) or birth defects. In many instances the same chromosomal abnormalities are found in one of their apparently unaffected parents. It suggests a reasonable question: why does a child have some problems, but his/her carrier-parent with the same deletion or duplication is healthy.

First of all we have to be convinced that a chromosomal defect found in a child is the cause of his/her problems. Of course, if the given deletion or duplication has been repeatedly found in a specific pathology group there are no doubts that this microanomaly is responsible for the child’s problems. Microanomalies in other families may be known as benign variants, and their role in the origin of the child’s pathology can be dismissed. In numerous instances, however, cytogenetic examinations show unique deletions or duplications, where the significance of the given microanomaly is still unknown. Such variants are usually called variants of unknown significance (VOUS). What can help to evaluate the role of each particular VOUS? 1) Genetic content. Variants with deletions (or duplications) involving several genes are potentially worse than variants with one gene. If a given variant does not include any genes then there are good reasons to consider it as a benign variant. 2) Size. Larger deletions (duplications) involve a larger number of genes and are potentially worse. 3) Deletions usually cause more harm than duplications of the same segment.

Sometimes, however, VOUS may be considered as a reason for the child’s problem without sufficient grounds. Actual problems in the patient may be caused by other factors (genetic or non-genetic) and VOUS inherited from a healthy parent may cause a question – why is the same variant found in an affected child and healthy parent. So, the first step – to be convinced that the microanomaly in the patient causes his/her problems.

But even if the deletion or duplication found in a child is known as pathogenic (for example, deletions 15q11q13, 16p11.2, etc.) there are numerous families where this abnormality is inherited from an apparently healthy mother or father. Every disorder (genetic or non-genetic) may have different manifestations in different persons. The same flu-virus may cause relatively mild symptoms in one person but may have grave consequences for another. Various manifestations are known for the patients having the same mutation of the same gene. It is relatively easy to differentiate “normal” and “abnormal” when we are dealing with birth defects (for example, polydactyly), but it is not so easy when we are dealing with conditions such as autism or anxiety. And in most families when the same deletion or duplication is found in a child and in the parent main reasons for child’s examination are neurobehavioral abnormalities rather than birth defects.

Assume that a normal IQ is between 80 and 120 (mean – 100), and in condition “A” the IQ will be between 60 and 100 (mean – 80). It is evident that among persons with condition “A” those with highest IQ will be considered as“normal”. They will have the best chances to be normally socially adapted, have their own families and produce their own children. But if their children inherit their “A” variant they will have mostly borderline IQs. The same is true for the persons with microdeletions or microduplications. Those who have best level of social adaptation will have the best chances to have their own families and own children, but those with an obvious disorder have more chances to remain childless. There are several studies which show minimal “pre-clinical” signs of abnormalities in apparently healthy carrier-parents (for example, some changes of personality characteristics in parents of autistic children). But because these abnormalities are “pre-clinical” such persons are considered to be healthy. So, minimal pre- clinical manifestations not recognizable as a disease may explain the existence of apparently healthy parents having the same microdeletion or microduplications as their affected children.

Another significant reason explaining the discrepancies in clinical manifestations in affected patients and non-affected parents is interactions between different genes. Assume that a given microdeletion includes the gene ABCD, which is responsible for an autosomal recessive condition. If the person having this microdeletion has a normal variant of the ABCD gene on another chromosome, he/she will be healthy. But if there is a mutation of this gene on another homologous chromosome, such a combination will produce a full picture of the disorder. Therefore, if the patient inherits the deleted chromosome from one of the parents and a chromosome with a mutated gene from another parent, the patient will be affected but the parent having the same microdeletion will be healthy. There are many examples of such combinations. Of course, the situation will become clear when (and if) the mutation in the homologous gene is found. Other forms of interaction may be even more complicated, and the clinical manifestations of the disease may require the participation of other genetic factors. For example, the clinical manifestations of the TAR syndrome (thrombocytopenia – absent radius) require not only the deletion of the 1q21.1 segment but also the involvement of the apparently innocent variant (single nucleotide polymorphism) in the RBM8A gene. There is no doubt that similar mechanisms may be involved in the origin of other conditions. Both subclinical manifestations and genetic interactions seem to be leading factors responsible for the phenomenon when an apparently healthy parent has the same chromosomal microanomaly as his/her affected child.