Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder

Abstract

BackgroundApparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.MethodsEighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.ResultsWe detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.ConclusionsThese findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

Copy number variations independently induce autism spectrum disorder

“…Several CNV studies in autism have identified associated genes and loci in European individuals and Han Chinese population controls [5][6][7][8]. Genetic studies on ASD in Han Chinese individuals have primarily been presented as case reports or association studies of particular common single nucleotide polymorphisms in ASD populations of European ancestry [9].…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…However, apparently 'balanced' SVs, which represent a small but significant number of cases, will thus escape detection [De Gregori et al, 2007;Hochstenbach et al, 2009]. With improving resolution of the CNV detecting arrays, the number of truly 'balanced' cases of SVs decreases, since the breakpoint regions of these SVs are increasingly found to contain small CNVs [Gribble et al, 2005;Fauth et al, 2006;De Gregori et al, 2007;Baptista et al, 2008;Higgins et al, 2008;Sismani et al, 2008;Schluth-Bolard et al, 2009;Gijsbers et al, 2010;Kang et al, 2010;Feenstra et al, 2011;Kloosterman et al, 2011Kloosterman et al, , 2012Tabet et al, 2015]. Also cases with multiple de novo or transmitted CNVs raise the suspicion of a CCR [Houge et al, 2003;Lybaek et al, 2008;Ballarati et al, 2009;Poot et al, 2009Poot et al, , 2010aSchluth-Bolard et al, 2009;Tzschach et al, 2010].…”

“…Classically, CCRs were extremely rare events detected by karyotyping [Madan et al, 1997;Park et al, 2001]. The implementation of genome-wide assays for segmental aneuploidy, such as BAC, oligonucleotide and SNP arrays, flow karyotyping, and nextgeneration sequencing techniques, has revealed an increasing complexity of CCRs [Gribble et al, 2005;Fauth et al, 2006;De Gregori et al, 2007;Baptista et al, 2008;Higgins et al, 2008;Sismani et al, 2008;Schluth-Bolard et al, 2009;Gijsbers et al, 2010;Kang et al, 2010;Feenstra et al, 2011;Kloosterman et al, 2011;Nazaryan et al, 2014;Tabet et al, 2015]. Not only the detection rate of CCRs increased, they were also more often associated with CNVs than reciprocal translocations were [Feenstra et al, 2011].…”

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

“…The absence of gross genomic imbalances renders BCAs invisible to higher resolution techniques that currently serve as first-tier diagnostic screens for many developmental anomalies of unknown etiology: chromosomal microarray (CMA), which can detect microscopic and sub-microscopic copy number variants (CNVs), or whole-exome sequencing (WES), which surveys single nucleotide variants within coding regions. We have recently shown that innovations in genomic technologies can efficiently reveal BCA breakpoints at nucleotide resolution with a cost and timeframe comparable to clinical CMA or karyotyping; however, only a limited number of BCAs have been evaluated to date 7,10–15 …”