Recent ultra-rare inherited variants implicate new autism candidate risk genes

Analysis of whole-genome sequence data from 3,474 families finds an excess of private, likely gene-disrupting variants in individuals with autism. These variants are under purifying selection and suggest candidate genes not previously associated with autism. Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.

Automated summary

Whole-genome sequencing data from 3,474 families revealed an excess of private, likely gene-disrupting variants in individuals with autism, which are under purifying selection. The study identified candidate genes not previously associated with autism and highlighted the importance of ultra-rare variants in autism risk. Private LGD variants were found to be significantly younger and act on a distinct set of genes, supporting a multi-hit model for autism.