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

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

485 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Pagina's (van-tot)	1063-1071
Aantal pagina's	9
Tijdschrift	Nature Genetics
Volume	46
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1038/ng.3092
Status	Gepubliceerd - 26 sep. 2014
Extern gepubliceerd	Ja

Toegang tot document

10.1038/ng.3092

Citeer dit

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

@article{8bbae565395e4ef0a675db5c1b8e5ebd,

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",

month = sep,

day = "26",

doi = "10.1038/ng.3092",

language = "English",

volume = "46",

pages = "1063--1071",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

}

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, nr. 10, blz. 1063-1071. https://doi.org/10.1038/ng.3092

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=84922012902&partnerID=8YFLogxK

U2 - 10.1038/ng.3092

DO - 10.1038/ng.3092

M3 - Article

C2 - 25217958

AN - SCOPUS:84922012902

SN - 1061-4036

VL - 46

SP - 1063

EP - 1071

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit