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

The SPARK Consortium

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1125-1134
Number of pages10
JournalNature genetics
Volume53
Issue number8
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'Recent ultra-rare inherited variants implicate new autism candidate risk genes'. Together they form a unique fingerprint.

Cite this