Identification of Small Exonic CNV from Whole-Exome Sequence Data and Application to Autism Spectrum Disorder

Abstract

Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes.

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

“…Cut-offs for CNV calling were also set at a minimum coverage of three markers/ probes per CNV, restricting downstream genetic and functional analyses to variants exceeding these minimum size thresholds. While more difficult to detect reliably by microarray approaches, small exonic CNVs of 1-30 kb have been suggested to contribute to susceptibility of some genetic diseases [71]. Finally, analyses were restricted to CNVs involving coding regions of at least one gene, ignoring variants solely impacting intronic or regulatory sequences.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Further studies found an enrichment of genes involved in MAPK signaling and neuronal development in autismassociated deletions [189]. Also, analysis of CNVs identified from WES data found an enrichment of cytoskeletal and autophagy genes in small CNVs in autism [190].…”

Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

“…[34][35][36][37] Meanwhile, genome-wide and microarray-based comparative genomic hybridizations have found that the CNV burden is also increased in patients with schizophrenia or autism-spectrum disorders compared with healthy controls. [38][39][40][41] For example, microduplications of 1q21.1 or 16p11.2 and deletions at 2p16.3, 15q11.2 or 22q11.21 have been reported in patients with schizophrenia and autism-spectrum disorders. 42 De novo gene-disrupting SNVs have also been found to occur at higher rates in patients with autismspectrum disorders than in controls.…”