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

被引：475

作者：

Coe, Bradley P. ^{[1
]}

Witherspoon, Kali ^{[1
]}

Rosenfeld, Jill A. ^{[2
]}

van Bon, Bregje W. M. ^{[3
,4
]}

Vulto-van Silfhout, Anneke T. ^{[3
]}

Bosco, Paolo ^{[5
]}

Friend, Kathryn L. ^{[4
]}

Baker, Carl ^{[1
]}

Buono, Serafino ^{[5
]}

Vissers, Lisenka E. L. M. ^{[3
]}

Schuurs-Hoeijmakers, Janneke H. ^{[3
]}

Hoischen, Alex ^{[3
]}

Pfundt, Rolph ^{[3
]}

Krumm, Nik ^{[1
]}

Carvill, Gemma L. ^{[6
]}

Li, Deana ^{[7
]}

Amaral, David ^{[7
]}

Brown, Natasha ^{[8
,9
]}

Lockhart, Paul J. ^{[8
,10
]}

Scheffer, Ingrid E. ^{[11
,12
]}

Alberti, Antonino ^{[5
]}

Shaw, Marie ^{[4
]}

Pettinato, Rosa ^{[5
]}

Tervo, Raymond ^{[13
]}

de Leeuw, Nicole ^{[3
]}

Reijnders, Margot R. F. ^{[3
]}

Torchia, Beth S. ^{[2
]}

Peeters, Hilde ^{[14
,15
]}

O'Roak, Brian J. ^{[1
]}

Fichera, Marco ^{[5
]}

Hehir-Kwa, Jayne Y. ^{[3
]}

Shendure, Jay ^{[1
]}

Mefford, Heather C. ^{[6
]}

Haan, Eric ^{[4
,16
]}

Gecz, Jozef ^{[4
,17
]}

de Vries, Bert B. A. ^{[3
]}

Romano, Corrado ^{[5
]}

Eichler, Evan E. ^{[1
,18
]}

机构：

[1] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[2] PerkinElmer Inc, Signature Genom Labs LLC, Spokane, WA USA

[3] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[4] SA Pathol, Adelaide, SA, Australia

[5] Associaz Oasi Maria Santissima, IRCCS, Troina, Italy

[6] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[7] Univ Calif Davis, MIND Inst, Autism Phenome Project, Sacramento, CA 95616 USA

[8] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Melbourne, Vic, Australia

[9] Barwon Hlth, Barwon Child Hlth Unit, Geelong, Vic, Australia

[10] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[11] Univ Melbourne, Austin Hlth, Florey Inst, Melbourne, Vic, Australia

[12] Royal Childrens Hosp, Melbourne, Vic, Australia

[13] Mayo Clin, Div Dev & Behav Pediat, Rochester, MN USA

[14] Katholieke Univ Leuven, Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium

[15] Leuven Autism Res LAuRes, Leuven, Belgium

[16] Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia

[17] Univ Adelaide, Robinson Inst, Adelaide, SA, Australia

[18] Howard Hughes Med Inst, Seattle, WA USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 10期

基金：

加拿大健康研究院;

关键词：

DE-NOVO MUTATIONS; AUTISM SPECTRUM DISORDER; SCHINZEL-GIEDION SYNDROME; INTELLECTUAL DISABILITY; MICRODELETION SYNDROME; MENTAL-RETARDATION; MOLECULAR CHARACTERIZATION; SEGMENTAL DUPLICATIONS; CLINICAL-SIGNIFICANCE; DELETIONS;

D O I：

10.1038/ng.3092

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1063 / 1071

页数：9

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