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Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.

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.

Pubmed ID: 23160955

Authors

  • O'Roak BJ
  • Vives L
  • Fu W
  • Egertson JD
  • Stanaway IB
  • Phelps IG
  • Carvill G
  • Kumar A
  • Lee C
  • Ankenman K
  • Munson J
  • Hiatt JB
  • Turner EH
  • Levy R
  • O'Day DR
  • Krumm N
  • Coe BP
  • Martin BK
  • Borenstein E
  • Nickerson DA
  • Mefford HC
  • Doherty D
  • Akey JM
  • Bernier R
  • Eichler EE
  • Shendure J

Journal

Science (New York, N.Y.)

Publication Data

December 21, 2012

Associated Grants

  • Agency: NICHD NIH HHS, Id: HD065285
  • Agency: NHLBI NIH HHS, Id: HL-102923
  • Agency: NHLBI NIH HHS, Id: HL-102924
  • Agency: NHLBI NIH HHS, Id: HL-102925
  • Agency: NHLBI NIH HHS, Id: HL-102926
  • Agency: NHLBI NIH HHS, Id: HL-103010
  • Agency: NINDS NIH HHS, Id: NS069605
  • Agency: NICHD NIH HHS, Id: R01 HD065285
  • Agency: NINDS NIH HHS, Id: R01 NS064077
  • Agency: NINDS NIH HHS, Id: R01 NS064077
  • Agency: NINDS NIH HHS, Id: R01 NS069605
  • Agency: NHLBI NIH HHS, Id: RC2 HL102926
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

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