Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

Brian O'Roak, Laura Vives, Wenqing Fu, Jarrett D. Egertson, Ian B. Stanaway, Ian G. Phelps, Gemma Carvill, Akash Kumar, Choli Lee, Katy Ankenman, Jeff Munson, Joseph B. Hiatt, Emily H. Turner, Roie Levy, Diana R. O'Day, Niklas Krumm, Bradley P. Coe, Beth K. Martin, Elhanan Borenstein, Deborah A. NickersonHeather C. Mefford, Dan Doherty, Joshua M. Akey, Raphael Bernier, Evan E. Eichler, Jay Shendure

Research output: Contribution to journalArticle

669 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1619-1622
Number of pages4
JournalScience
Volume338
Issue number6114
DOIs
StatePublished - Dec 21 2012
Externally publishedYes

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Genes
Megalencephaly
Exome
Molecular Probes
Catenins
Microcephaly
Mutation
Chromatin Assembly and Disassembly
Autism Spectrum Disorder
Costs and Cost Analysis
Proteins

ASJC Scopus subject areas

  • General

Cite this

O'Roak, B., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., ... Shendure, J. (2012). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science, 338(6114), 1619-1622. https://doi.org/10.1126/science.1227764

Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. / O'Roak, Brian; Vives, Laura; Fu, Wenqing; Egertson, Jarrett D.; Stanaway, Ian B.; Phelps, Ian G.; Carvill, Gemma; Kumar, Akash; Lee, Choli; Ankenman, Katy; Munson, Jeff; Hiatt, Joseph B.; Turner, Emily H.; Levy, Roie; O'Day, Diana R.; Krumm, Niklas; Coe, Bradley P.; Martin, Beth K.; Borenstein, Elhanan; Nickerson, Deborah A.; Mefford, Heather C.; Doherty, Dan; Akey, Joshua M.; Bernier, Raphael; Eichler, Evan E.; Shendure, Jay.

In: Science, Vol. 338, No. 6114, 21.12.2012, p. 1619-1622.

Research output: Contribution to journalArticle

O'Roak, B, 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 2012, 'Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders', Science, vol. 338, no. 6114, pp. 1619-1622. https://doi.org/10.1126/science.1227764
O'Roak, Brian ; Vives, Laura ; Fu, Wenqing ; Egertson, Jarrett D. ; Stanaway, Ian B. ; Phelps, Ian G. ; Carvill, Gemma ; Kumar, Akash ; Lee, Choli ; Ankenman, Katy ; Munson, Jeff ; Hiatt, Joseph B. ; Turner, Emily H. ; Levy, Roie ; O'Day, Diana R. ; Krumm, Niklas ; Coe, Bradley P. ; Martin, Beth K. ; Borenstein, Elhanan ; Nickerson, Deborah A. ; Mefford, Heather C. ; Doherty, Dan ; Akey, Joshua M. ; Bernier, Raphael ; Eichler, Evan E. ; Shendure, Jay. / Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. In: Science. 2012 ; Vol. 338, No. 6114. pp. 1619-1622.
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AU - Mefford, Heather C.

AU - Doherty, Dan

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