Recurrent de novo mutations implicate novel genes underlying simplex autism risk

Abstract

Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.

Figure 1. smMIP resequencing of 64 genes implicates specific genes in ASD

(a) Quantile-Quantile plot comparing the individual gene recurrence mutation simulation results from the MIP-only samples (2,757 ASD probands, 1,733 unaffected siblings) to a uniform distribution (Methods). Proband data are plotted in red, sibling data in blue. Proband data implicate nine genes as significantly disrupted in ASD. Dashed line indicates a Holm-Bonferroni corrected significance level. (b) Protein diagrams of five genes with significant recurrent de novo mutations. Annotated protein domains are shown (colored blocks) for the largest protein isoforms. Mutations shown above the protein structure were newly identified in this study using MIPs. Mutations shown below the protein structure have been previously reported from exome sequencing of ASD/ID cohorts or MIP-based resequencing. Red variants are nonsense, frameshifting, or splice site. Domain abbreviations: ZNFC2, zinc finger; NLS, nuclear localization signal; HOX, homeodomain; CHROMO, chromatin organization modifier; DEXDc, DEAD-like helicases superfamily; HELIC, helicase superfamily C-terminal; CC, coiled coil; PH, pleckstrin homology; RASGAP, GTPase-activator for Ras-like GTPases; HECT, homologous to E6-AP carboxyl terminus; PAX, paired box.