Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders

Neuron. 2013 Jan 23;77(2):235-42. doi: 10.1016/j.neuron.2012.12.029.

Abstract

To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Child Development Disorders, Pervasive / diagnosis*
  • Child Development Disorders, Pervasive / epidemiology
  • Child Development Disorders, Pervasive / genetics*
  • Child, Preschool
  • Chromosomes, Human, X / genetics
  • Demography / methods*
  • Female
  • Gene Deletion*
  • Genetic Variation / genetics
  • Homozygote
  • Humans
  • Linkage Disequilibrium / genetics
  • Loss of Heterozygosity / genetics*
  • Male
  • Risk Factors

Grant support