Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk

Abstract

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.

Figure 1. Copy number variations identified in 11 families.

A–E) Five extended ASD families had deletions segregating with disease. F–K) Six ASD families carried duplications that segregated with ASD. Family 17122 had two duplications that were inherited in an identical manner (H). Only individuals marked with a small circle had DNA available for testing.

Figure 2. Prioritization of copy number variations of interest.

Structural variants were first assessed to determine whether they were present in our control individuals or the Database of Genomic Variants. Literature searches were then performed to determine if the CNVs we identified were previously reported as ASD regions with similar breakpoints or overlay with larger ASD reported regions. Higher priority was given to variation absent in controls and those that fell within regions previously connected to ASDs. Low frequency CNVs were identified in our control HIHG and NBC dataset, but at a frequency below 1.5%. Duplications are in green and deletions are in red.

Figure 3. Copy number variations that intersect genes.

A,B) Deletions on 1p34.1 and 6q11.1 fall within the intronic regions of ZSWIM5 and KHDRBS2, respectively. C–F) Four duplications on 4p16.3, 7p21.3, 10q 23.2, and 15q24.1 completely encompass the FGFPB3 and TNIP2 genes and traverse portions of BTAF1, ICA1, NXPH1, and UBL7. Deletions are denoted with red bars, duplications marked by green bars and genes are annotated with blue lines. Genes that intersect CNVs are in bold.