Transmission Disequilibrium of Small CNVs in Simplex Autism

Abstract

We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.

Copy-number variations are enriched for neurodevelopmental genes in children with developmental coordination disorder

“…To reduce the number of false-positive CNV calls, a lower CNV size limit of 20 kb was used in the case–control analyses. The analysis of small CNVs detected by next-generation sequencing in a simplex autism cohort identified a higher gene density in participants with autism, suggesting a role for small CNVs in understanding the genetics of neurodevelopmental disorders 32. As such, further analysis of CNVs smaller than 20 kb in a larger cohort of DCD participants is warranted.…”

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

“…Among those was a CNV deletion (1.9 Mb) of exons 1-23 of PCDH15, which has been reported as a risk factor for neurobehavioural disorders, [35][36][37][38] in a 44-year-old participant with a family history of attention-deficit/ hyperactivity disorder. Despite an extensive literature review, we concluded that 4 other variants -in ANK2, CDH1, CHMP2B and KCNE2 -had uncertain clinical significance (Table 3).…”

Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: On the path to an animal model of attention-deficit hyperactivity disorder

“…Key to the findings is the de novo status of the variant. ASD has been found to exhibit an increased number of de novo variants (Kenny et al, 2013; Jiang et al, 2013), including copy number variants (CNVs) (Griswold et al, 2012; Holt et al, 2012; Krumm et al, 2013; Menashe et al, 2013; Poultney et al, 2013; Vaishnavi et al, 2013) as well as single nucleotide polymorphisms (SNPs). Because de novo coding mutations are low in probability, particularly in the coding regions of genes, geneticists consider de novo variations to be of particular significance in establishing genetic risk.…”