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

Bradley P. Coe; Kali Witherspoon; Jill A. Rosenfeld; Bregje W.M. Van Bon; Anneke T. Vulto-Van Silfhout; Paolo Bosco; Kathryn L. Friend; Carl Baker; Serafino Buono; Lisenka E.L.M. Vissers; Janneke H. Schuurs-Hoeijmakers; Alex Hoischen; Rolph Pfundt; Nik Krumm; Gemma L. Carvill; Deana Li; David Amaral; Natasha Brown; Paul J. Lockhart; Ingrid E. Scheffer; Antonino Alberti; Marie Shaw; Rosa Pettinato; Raymond Tervo; Nicole De Leeuw; Margot R.F. Reijnders; Beth S. Torchia; Hilde Peeters; Elizabeth Thompson; Brian J. O'Roak; Marco Fichera; Jayne Y. Hehir-Kwa; Jay Shendure; Heather C. Mefford; Eric Haan; Jozef Gécz; Bert B.A. De Vries; Corrado Romano; Evan E. Eichler

doi:10.1038/ng.3092

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

Bradley P. Coe, Kali Witherspoon, Jill A. Rosenfeld, Bregje W.M. Van Bon, Anneke T. Vulto-Van Silfhout, Paolo Bosco, Kathryn L. Friend, Carl Baker, Serafino Buono, Lisenka E.L.M. Vissers, Janneke H. Schuurs-Hoeijmakers, Alex Hoischen, Rolph Pfundt, Nik Krumm, Gemma L. Carvill, Deana Li, David Amaral, Natasha Brown, Paul J. Lockhart, Ingrid E. SchefferAntonino Alberti, Marie Shaw, Rosa Pettinato, Raymond Tervo, Nicole De Leeuw, Margot R.F. Reijnders, Beth S. Torchia, Hilde Peeters, Elizabeth Thompson, Brian J. O'Roak, Marco Fichera, Jayne Y. Hehir-Kwa, Jay Shendure, Heather C. Mefford, Eric Haan, Jozef Gécz, Bert B.A. De Vries, Corrado Romano, Evan E. Eichler

Molecular and Medical Genetics

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1063-1071
Number of pages	9
Journal	Nature genetics
Volume	46
Issue number	10
DOIs	https://doi.org/10.1038/ng.3092
State	Published - Sep 26 2014

ASJC Scopus subject areas

Genetics

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Coe, B. P., Witherspoon, K., Rosenfeld, J. A., Van Bon, B. W. M., Vulto-Van Silfhout, A. T., Bosco, P., Friend, K. L., Baker, C., Buono, S., Vissers, L. E. L. M., Schuurs-Hoeijmakers, J. H., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G. L., Li, D., Amaral, D., Brown, N., Lockhart, P. J., ... Eichler, E. E. (2014). Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature genetics, 46(10), 1063-1071. https://doi.org/10.1038/ng.3092

Coe, BP, Witherspoon, K, Rosenfeld, JA, Van Bon, BWM, Vulto-Van Silfhout, AT, Bosco, P, Friend, KL, Baker, C, Buono, S, Vissers, LELM, Schuurs-Hoeijmakers, JH, Hoischen, A, Pfundt, R, Krumm, N, Carvill, GL, Li, D, Amaral, D, Brown, N, Lockhart, PJ, Scheffer, IE, Alberti, A, Shaw, M, Pettinato, R, Tervo, R, De Leeuw, N, Reijnders, MRF, Torchia, BS, Peeters, H, Thompson, E, O'Roak, BJ, Fichera, M, Hehir-Kwa, JY, Shendure, J, Mefford, HC, Haan, E, Gécz, J, De Vries, BBA, Romano, C & Eichler, EE 2014, 'Refining analyses of copy number variation identifies specific genes associated with developmental delay', Nature genetics, vol. 46, no. 10, pp. 1063-1071. https://doi.org/10.1038/ng.3092

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title = "Refining analyses of copy number variation identifies specific genes associated with developmental delay",

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.",

author = "Coe, {Bradley P.} and Kali Witherspoon and Rosenfeld, {Jill A.} and {Van Bon}, {Bregje W.M.} and {Vulto-Van Silfhout}, {Anneke T.} and Paolo Bosco and Friend, {Kathryn L.} and Carl Baker and Serafino Buono and Vissers, {Lisenka E.L.M.} and Schuurs-Hoeijmakers, {Janneke H.} and Alex Hoischen and Rolph Pfundt and Nik Krumm and Carvill, {Gemma L.} and Deana Li and David Amaral and Natasha Brown and Lockhart, {Paul J.} and Scheffer, {Ingrid E.} and Antonino Alberti and Marie Shaw and Rosa Pettinato and Raymond Tervo and {De Leeuw}, Nicole and Reijnders, {Margot R.F.} and Torchia, {Beth S.} and Hilde Peeters and Elizabeth Thompson and O'Roak, {Brian J.} and Marco Fichera and Hehir-Kwa, {Jayne Y.} and Jay Shendure and Mefford, {Heather C.} and Eric Haan and Jozef G{\'e}cz and {De Vries}, {Bert B.A.} and Corrado Romano and Eichler, {Evan E.}",

year = "2014",

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doi = "10.1038/ng.3092",

language = "English (US)",

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T1 - Refining analyses of copy number variation identifies specific genes associated with developmental delay

AU - Coe, Bradley P.

AU - Witherspoon, Kali

AU - Rosenfeld, Jill A.

AU - Van Bon, Bregje W.M.

AU - Vulto-Van Silfhout, Anneke T.

AU - Bosco, Paolo

AU - Friend, Kathryn L.

AU - Baker, Carl

AU - Buono, Serafino

AU - Vissers, Lisenka E.L.M.

AU - Schuurs-Hoeijmakers, Janneke H.

AU - Hoischen, Alex

AU - Pfundt, Rolph

AU - Krumm, Nik

AU - Carvill, Gemma L.

AU - Li, Deana

AU - Amaral, David

AU - Brown, Natasha

AU - Lockhart, Paul J.

AU - Scheffer, Ingrid E.

AU - Alberti, Antonino

AU - Shaw, Marie

AU - Pettinato, Rosa

AU - Tervo, Raymond

AU - De Leeuw, Nicole

AU - Reijnders, Margot R.F.

AU - Torchia, Beth S.

AU - Peeters, Hilde

AU - Thompson, Elizabeth

AU - O'Roak, Brian J.

AU - Fichera, Marco

AU - Hehir-Kwa, Jayne Y.

AU - Shendure, Jay

AU - Mefford, Heather C.

AU - Haan, Eric

AU - Gécz, Jozef

AU - De Vries, Bert B.A.

AU - Romano, Corrado

AU - Eichler, Evan E.

PY - 2014/9/26

Y1 - 2014/9/26

N2 - 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.

AB - 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.

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JF - Nature genetics

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ER -

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

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