Refining analyses of copy number variation identifies specific genes associated with developmental delay

Nat Genet. 2014 Oct;46(10):1063-71. doi: 10.1038/ng.3092. Epub 2014 Sep 14.

Abstract

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Publication types

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

MeSH terms

  • Autistic Disorder / genetics*
  • Base Sequence
  • Carrier Proteins / genetics
  • Child
  • Chromosome Mapping
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations*
  • Developmental Disabilities / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Haploinsufficiency / genetics
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA

Substances

  • Carrier Proteins
  • Nuclear Proteins
  • SETBP1 protein, human
  • ZMYND11 protein, human

Associated data

  • dbVar/nsdt100