Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

Brian J. 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. Nickerson; Heather C. Mefford; Dan Doherty; Joshua M. Akey; Raphael Bernier; Evan E. Eichler; Jay Shendure

doi:10.1126/science.1227764

Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

Brian J. 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

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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 language	English (US)
Pages (from-to)	1619-1622
Number of pages	4
Journal	Science
Volume	338
Issue number	6114
DOIs	https://doi.org/10.1126/science.1227764
State	Published - Dec 21 2012
Externally published	Yes

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O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., Turner, E. H., Levy, R., O'Day, D. R., Krumm, N., Coe, B. P., Martin, B. K., Borenstein, E., ... 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

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 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

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title = "Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders",

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.",

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

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AU - O'Roak, Brian J.

AU - Vives, Laura

AU - Fu, Wenqing

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AU - Stanaway, Ian B.

AU - Phelps, Ian G.

AU - Carvill, Gemma

AU - Kumar, Akash

AU - Lee, Choli

AU - Ankenman, Katy

AU - Munson, Jeff

AU - Hiatt, Joseph B.

AU - Turner, Emily H.

AU - Levy, Roie

AU - O'Day, Diana R.

AU - Krumm, Niklas

AU - Coe, Bradley P.

AU - Martin, Beth K.

AU - Borenstein, Elhanan

AU - Nickerson, Deborah A.

AU - Mefford, Heather C.

AU - Doherty, Dan

AU - Akey, Joshua M.

AU - Bernier, Raphael

AU - Eichler, Evan E.

AU - Shendure, Jay

PY - 2012/12/21

Y1 - 2012/12/21

N2 - 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.

AB - 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.

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Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

Abstract

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