Using Large Clinical Data Sets to Infer Pathogenicity for Rare Copy Number Variants in Autism Cohorts

Mol Psychiatry. 2013 Oct;18(10):1090-5. doi: 10.1038/mp.2012.138. Epub 2012 Oct 9.

Abstract

Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.

Publication types

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

MeSH terms

  • Autistic Disorder / epidemiology
  • Autistic Disorder / genetics
  • Causality
  • Child Development Disorders, Pervasive / epidemiology
  • Child Development Disorders, Pervasive / genetics*
  • Congenital Abnormalities / epidemiology
  • Congenital Abnormalities / genetics
  • Data Mining
  • Developmental Disabilities / epidemiology
  • Developmental Disabilities / genetics
  • Gene Deletion
  • Gene Dosage*
  • Gene Duplication
  • Genetic Association Studies
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Homologous Recombination
  • Humans
  • Prevalence
  • Sample Size