Recurrent 15q11.2 BP1‐BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders

Abstract

Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples. © 2016 Wiley Periodicals, Inc.

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

“…It also exemplifies the variability of phenotypic expression even within a known abnormality, already observed in many studies of these specific genetic disorders (17). While it would be interesting to make observations about the most common dnLoFs and dnCNVs, which included four CNV duplications, one CNV deletion, and two mutations all previously associated with ASD, there are published “genetics first” cohorts for each of these (17, 18, 20, 37–39). These studies describe wide within-cohort variability in phenotypic expression, based on type of mutation or CNV characteristics such as deletion versus duplication, size of the error, and the specific genes involved (2).…”

The Belgian MicroArray Prenatal (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations

“…The 15q11.2 duplication (chr15:22800000–23090000, minimal size 290 kb) is the most frequently found unreported susceptibility CNV in our population (32 cases). The phenotypic spectrum of developmental delay is highly variable, from motor coordination problems to autism spectrum disorder and obsessive compulsive disorder . Although initially described as a susceptibility region for neurological dysfunction, several more recent reports failed to show a clear genotype–phenotype association.…”

“…The phenotypic spectrum of developmental delay is highly variable, from motor coordination problems to autism spectrum disorder and obsessive compulsive disorder. 25 Although initially described as a susceptibility region for neurological dysfunction, 17 several more recent reports failed to show a clear genotype-phenotype association. Cooper described 64/15 767 patients with developmental delay versus 36/8 329 healthy controls (penetrance 0.64), 13 Coe detected the 15q11.2 duplication in 128/29 085 patients with developmental delay versus 60/19 584 healthy controls, resulting in a likelihood ratio of 1.44.…”

A Rare Case of Concomitant Deletions in 15q11.2 and 19p13.3

“…The patient's deletion in 15q11.2 is 507 kb in size between BP1 and BP2 regions and encompasses 7 genes, of which 4, NIPA1 (OMIM 608145), NIPA 2 (OMIM 608146), CYFIP1 (OMIM 606322), and TUBGCP5 (OMIM 608147) are catalogued in the OMIM database and are not imprinted [Burnside et al, 2011;Picinelli et al, 2016]. There is an estimated phenotypic penetrance of only 10.4% for 15q11.2 deletions, which means that there is a 90% likelihood for normal phenotype [Rosenfeld et al, 2013].…”