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Recent ultra-rare inherited mutations identify novel autism candidate risk genes

Wilfert, A. B.; Turner, T. N.; Murali, S. C.; Hsieh, P.; Sulovari, A.; Wang, T.; Coe, B. P.; Guo, H.; Hoekzema, K.; Bakken, T. E.; Winterkorn, L. H.; Evani, U. S.; Byrska-Bishop, M.; Earl, R. K.; Bernier, R. A.; The SPARK Consortium, ; Zody, M. C.; Eichler, E. E.

2020-02-11 genetics
10.1101/2020.02.10.932327 bioRxiv
Show abstract

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. One sentence summaryUltra-rare autism variants preferentially transmitted to probands are younger and identify distinct gene candidates and functional networks.

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