Recent ultra-rare inherited mutations identify novel autism candidate risk genes
Amy B Wilfert,
Tychele N. Turner,
Shwetha C. Murali,
Bradley P. Coe,
Trygve E Bakken,
Lara H Winterkorn,
Uday S Evani,
Rachel K Earl,
Raphael A. Bernier,
The SPARK Consortium,
Michael C. Zody,
Evan E. Eichler
Posted 11 Feb 2020
bioRxiv DOI: 10.1101/2020.02.10.932327
Posted 11 Feb 2020
Autism is a highly heritable, complex disorder where de novo mutation (DNM) variation contributes significantly to disease risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare mutations. We report and replicate a transmission disequilibrium of private likely-gene disruptive (LGD) mutations 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 these mutations are ~2.5 generations old and significantly younger than other mutations of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and act on a distinct set of genes not yet associated with autism.
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