Details

Autor(en) / Beteiligte

• Wilfert, Amy B.
• Turner, Tychele N.
• Murali, Shwetha C.
• Hsieh, PingHsun
• Sulovari, Arvis
• Wang, Tianyun
• Coe, Bradley P.
• Guo, Hui
• Hoekzema, Kendra
• Bakken, Trygve E.
• Winterkorn, Lara H.
• Evani, Uday S.
• Byrska-Bishop, Marta
• Earl, Rachel K.
• Bernier, Raphael A.
• Zody, Michael C.
• Eichler, Evan E.

Titel

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

Ist Teil von

• Nature genetics, 2021-07, Vol.53 (8), p.1125-1134

Erscheinungsjahr

2021

Beschreibungen/Notizen

• Autism is a highly heritable complex disorder where 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 these variants are ~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.