13
Mar

1p36 Deletion Syndrome

1p36 Deletion Syndrome (Monosomy 1p36)

Mapped location of 1p36 on Chromosome 1

Occurring in 1 out of 5,000-10,000 live births, monosomy 1p36 is the most common subtelomeric deletion syndrome in humans1. The first reports of individuals with partial monosomy of chromosome 1p36 were published in the early 1980s2. Identifying patients with monosomy 1p36 may be difficult because characteristic dysmorphic features are sometimes subtle or missing, congenital anomalies are numerous, and none seem to be pathognomonic or systematically present3.

Common features associated with this syndrome include developmental delay (severe to profound in a majority), hypotonia (low muscle tone), microcephaly (abnormally small head), and characteristic dysmorphic facial features consisting of midface hypoplasia (underdevelopment), broad nasal root, deep-set eyes, straight eyebrows, pointed chin, large, late-closing anterior fontanelle1). Developmental delays are variable but present in all individuals2. Brachydactyly (short fingers and toes) and short feet are also common3. Hypotonia and seizures are seen in more than one-half of affected patients4. Nearly all patients have EEG abnormalities but only 44%-58% have clinical seizures5. Hearing loss and vision problems are seen in one-half of individuals, and renal abnormalities are seen in one-quarter4.

Significant part of patients with deletion 1p36 has heart defects – both structural and functional. Spectrum of structural heart defects is similar to the same in general population, most of them are not life threatening. At least ¼ of patients have cardiomyopathies – functional defects which may be found both in persons with and without structural heart abnormalities. The most common form is left ventricular noncompaction (LVNC). Association of LVNC with increased size of heart ventricles and diminished systolic function may lead to dilated cardiomyopathy (DCM). Although PRDM16 gene is considered the main player for DCM in patients with 1p36 deletion6, other genes in this area may also contribute to the development of this condition7.

Most genes contributing to the phenotypic features of 1p36 deletion syndrome are located distal to marker D1S2870 (chr1:6,289,764–6,289,973), this region is subsequently referred to as the distal or classical critical region2. Some of the most strongly implicated 1p36 genes include MMP23B, GABRD, SKI, PRDM16,KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1,HSPG2, and LUZP12. Although, genes that contribute to most 1p36-related phenotypes have yet to be identified, many 1p36-related phenotypes may arise from haploinsufficiency (only one copy of a gene) for more than one gene within a particular genomic region2.

There is marked variability in the deletions of 1p36 , with no common breakpoints or deletion sizes1. Although a majority (52%) of deletions are pure terminal deletions, interstitial deletions (29%), complex rearrangements with multiple deletions and/or duplications (12%), and unbalanced translocations (exchange of chromosome material causing extra or missing genes) (7%) are also seen1. Despite this genotypic variability, there is a relatively consistent phenotypic presentation, and patients with non-overlapping deletions have been reported to have similar features1. Affected children are particularly weak at language expression (speech). Behavioral disorders are present in 50% of affected individuals5. These include poor social interaction, temper tantrums, self-biting, stereotypies and less commonly hyperphagia (abnormally increased appetite for food)5.

According to the published clinical studies, brain abnormalities occur in 60-88% of the patients3. The most frequent findings indicating brain mal- or dysformation include diffuse (generalized) brain atrophy (degeneration), cortical atrophy, micropolygyria (neuronal migration disorder), focal pachygyria, and enlargement of the lateral ventricles3. In some cases, brain imaging demonstrated shared findings of white matter abnormalities involving periventricular and subcortical areas emerging in different ages predominantly in the parietal lobes (related to sensory processing)3.

Because deletions 1p36 in significant part of patients are caused by parental rearrangements (translocations or more complex abnormalities) examination of the parental karyotypes is necessary, especially for the families planning further children. Prenatal diagnosis may require molecular cytogenetic examination of the fetus, because “standard” cytogenetic tests may be not sensitive enough to detect deletion 1p36.

 

References

1Rosenfeld JA, et al. Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions. Am J Med Genet 2010, 152A:1951–1959.

2 Jordan VK, et al. 1p36 deletion syndrome: an update. Applications Clin Genet 2015, 8:189-200.

3Oiglane-Shlik E, et al. Monosomy 1p36 – A multifaceted and still enigmatic syndrome: Four clinically diverse cases
with shared white matter abnormalities. Eur J Paed Neurol 2014, 18:338-346.

4Battaglia A, et al. Further delineation of deletion 1p36 syndrome in 60 patients: A recognizable phenotype and
common cause of developmental delay and mental retardation. Pediatrics 2008, 121:404-410.

5Chan YTP, et al. Answer to “Clinical Quiz”. HK J Paediatr (New Series) 2015, 20:212-214.

6Arndt A-K, et al. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of
cardiomyopathy. Am J Hum Genet 2013, 93: 67-77.

7Zaveri HP, et al. Identification of critical regions and candidate genes for cardiovascular malformations and
cardiomyopathy associated with deletions of chromosome 1p36. PLOS ONE 2014, 9:e85600.

Author: Author: Colleen Donnelly

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