Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

Science. 2012 Dec 21;338(6114):1619-22. doi: 10.1126/science.1227764. Epub 2012 Nov 15.

Abstract

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.

Publication types

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

MeSH terms

  • Cephalometry
  • Child
  • Child Development Disorders, Pervasive / genetics*
  • Child, Preschool
  • Chromatin Assembly and Disassembly
  • Cohort Studies
  • DNA Probes
  • DNA-Binding Proteins / genetics
  • Exome
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Megalencephaly / genetics
  • Microcephaly / genetics
  • Mutation*
  • Nuclear Proteins / genetics
  • PTEN Phosphohydrolase / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Tyrosine Kinases / genetics
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, DNA / methods*
  • T-Box Domain Proteins / genetics
  • Transcription Factors / genetics
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • CHD8 protein, human
  • DNA Probes
  • DNA-Binding Proteins
  • NR2B NMDA receptor
  • Nuclear Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, N-Methyl-D-Aspartate
  • Repressor Proteins
  • T-Box Domain Proteins
  • TBL1XR1 protein, human
  • TBR1 protein, human
  • Transcription Factors
  • beta Catenin
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human