Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci

Abstract

BackgroundAutism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism.MethodsAs copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members.ResultsResults include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions.ConclusionsThese results provide additional support for the role of rare structural variation in ASD.

Identification of Rare Recurrent Copy Number Variants in High-Risk Autism Families and Their Prevalence in a Large ASD Population

“…Contrary to our findings, a recent search for CNVs in GABA pathway genes [44] did not find an enrichment of duplications in this region. Rather, both deletions and duplications were observed at similar frequencies in cases and controls.…”

“…In contrast to our findings, this study found GABR gene cluster duplications at similar frequencies in both cases and in controls (Table S2 in ref. [44]). In addition, deletions were more common in this study in both cases and controls, while duplications were more common in our data.…”

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion

“…These deletions involve different molecular regions: the a isoform is affected in cases 1 and 3, whereas a and b isoforms are affected in case 2. Defects involving NRXN1-b appear to be rare compared to those involving only NRXN1-a (Duong et al 2012;Dabell et al 2013)Approximately 101 cases of CNVs in 2p16.3 including the NRXN1 gene have been described, 95 deletions and 6 duplications, with a mean size of 388.97 kb (Friedman et al 2006;Szatmari et al 2007;Kirov et al 2008;Zahir et al 2008;Rujescu et al 2009;Ching et al 2010;Magri et al 2010;Wisniowiecka-Kowalnik et al 2010;Duong et al 2012;Hedges et al 2012;Schaaf et al 2012;Bena et al 2013). The a isoform is affected in all cases, whereas the b isoform is additionally affected in only 21 cases.…”

Accurate detection of complex structural variations using single molecule sequencing

“…Structural variations (SVs), including deletions, duplications, insertions, inversions and translocations of at least 50bp, account for the largest number of divergent base pairs (bp) across human genomes 1 . SVs have been shown to contribute to polymorphic variation, pathogenic conditions, and large-scale chromosome evolution 2 , and several human diseases such as cancer 3 , autism 4 , or Alzheimer's 5 have been associated with SVs. SVs have also been shown to impact phenotypes for an increasing number of other organisms [6][7][8][9][10] .…”