Genome sequencing identifies major causes of severe intellectual disability

Nature. 2014 Jul 17;511(7509):344-7. doi: 10.1038/nature13394. Epub 2014 Jun 4.

Abstract

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomes, Human, Pair 4 / genetics
  • Chromosomes, Human, X / genetics
  • Cohort Studies
  • DNA Copy Number Variations / genetics*
  • Gene Duplication / genetics
  • Genome, Human / genetics*
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mutation / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Sequence Analysis, DNA*

Substances

  • Guanine Nucleotide Exchange Factors
  • IQSEC2 protein, human