Publications

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

Autism is a highly heritable complex disorder in which 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 that these variants are approximately 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.

Nat Genet. 2021 Aug;53(8):1125-1134. doi: 10.1038/s41588-021-00899-8. Epub 2021 Jul 26.

Authors

Other Contributors

Amy B Wilfert 1, Tychele N Turner 1 2, Shwetha C Murali 1 3, PingHsun Hsieh 1, Arvis Sulovari 1, Tianyun Wang 1, Bradley P Coe 1, Hui Guo 1 4, Kendra Hoekzema 1, Trygve E Bakken 5, Lara H Winterkorn 6, Uday S Evani 6, Marta Byrska-Bishop 6, Rachel K Earl 7, Raphael A Bernier 7, SPARK Consortium; Michael C Zody 6, Evan E Eichler 8 9

Collaborators

SPARK Consortium:
Xueya Zhou, Pamela Feliciano, Jacob Hall, Irina Astrovskaya, Simon Xu, Chang Shu, Joseph Obiajulu, Leo Brueggeman, Jessica Wright, Olena Marchenko, Chris Fleisch, Timothy S Chang, LeeAnne Green Snyder, Sarah D Barns, Bing Han, William Harvey, Andrew Nishida, Ryan Doan, Aubrey Soucy, Brian J O’Roak, Timothy W Yu, Daniel Geschwind, Jacob Michaelson, Natalia Volfovsky, Yufeng Shen, Wendy K Chung

Affiliations

  • 1Department of Genome Sciences, University of
    Washington School of Medicine, Seattle, WA, USA.
  • 2Department of Genetics, Washington University
    School of Medicine, St. Louis, MO, USA.
  • 3Howard Hughes Medical Institute, University of
    Washington, Seattle, WA, USA.
  • 4Center for Medical Genetic & Hunan Key
    Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
  • 5Allen Institute for Brain Science, Seattle, WA,
    USA.
  • 6New York Genome Center, New York, NY, USA.
  • 7Department of Psychiatry and Behavioral Sciences,
    University of Washington, Seattle, WA, USA.
  • 8Department of Genome Sciences, University of
    Washington School of Medicine, Seattle, WA, USA.
  • 9Howard Hughes Medical Institute, University of
    Washington, Seattle, WA, USA.

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