1. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.
- Author
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Zhou X, Feliciano P, Shu C, Wang T, Astrovskaya I, Hall JB, Obiajulu JU, Wright JR, Murali SC, Xu SX, Brueggeman L, Thomas TR, Marchenko O, Fleisch C, Barns SD, Snyder LG, Han B, Chang TS, Turner TN, Harvey WT, Nishida A, O'Roak BJ, Geschwind DH, Michaelson JJ, Volfovsky N, Eichler EE, Shen Y, and Chung WK
- Subjects
- Exome genetics, Forkhead Transcription Factors genetics, Genetic Predisposition to Disease, Humans, Mutation, Repressor Proteins genetics, Exome Sequencing, Autism Spectrum Disorder genetics, Autistic Disorder genetics
- Abstract
To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10
-6 ), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6 ). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes., (© 2022. The Author(s).)- Published
- 2022
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