Recent ultra-rare inherited variants implicate new autism candidate risk genes.
Recent ultra-rare inherited variants implicate new autism candidate risk genes.
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DOI：
10.1038/s41588-021-00899-8
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发表时间：
2021-08
期刊：
影响因子：
30.8
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Wilfert AB;Turner TN;Murali SC;Hsieh P;Sulovari A;Wang T;Coe BP;Guo H;Hoekzema K;Bakken TE;Winterkorn LH;Evani US;Byrska-Bishop M;Earl RK;Bernier RA;SPARK Consortium;Zody MC;Eichler EE
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.
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影响因子：
14.9
作者：
Dougherty JD;Schmidt EF;Nakajima M;Heintz N
通讯作者：
Heintz N
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
5.3
作者：
Snijders Blok L;Hiatt SM;Bowling KM;Prokop JW;Engel KL;Cochran JN;Bebin EM;Bijlsma EK;Ruivenkamp CAL;Terhal P;Simon MEH;Smith R;Hurst JA;DDD study;McLaughlin H;Person R;Crunk A;Wangler MF;Streff H;Symonds JD;Zuberi SM;Elliott KS;Sanders VR;Masunga A;Hopkin RJ;Dubbs HA;Ortiz-Gonzalez XR;Pfundt R;Brunner HG;Fisher SE;Kleefstra T;Cooper GM
通讯作者：
Cooper GM
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
30.8
作者：
Coe, Bradley P.;Stessman, Holly A. F.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.