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Nat Genet. 2014 Oct;46(10):1063-71. doi: 10.1038/ng.3092. Epub 2014 Sep 14.

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

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
2
Signature Genomics Laboratories, LLC, PerkinElmer, Inc., Spokane, Washington, USA.
3
1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. [2] SA Pathology, North Adelaide, South Australia, Australia.
4
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
5
IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
6
SA Pathology, North Adelaide, South Australia, Australia.
7
Department of Pediatrics, University of Washington, Seattle, Washington, USA.
8
Representing the Autism Phenome Project, MIND Institute, University of California, Davis, Sacramento, California, USA.
9
1] Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. [2] Barwon Child Health Unit, Barwon Health, Geelong, Victoria, Australia.
10
1] Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. [2] Murdoch Childrens Research Institute, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
11
Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia.
12
Division of Developmental and Behavioral Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
13
1] Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. [2] Leuven Autism Research (LAuRes), Leuven, Belgium.
14
1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2].
15
1] IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy. [2].
16
1] SA Pathology, North Adelaide, South Australia, Australia. [2] School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
17
1] SA Pathology, North Adelaide, South Australia, Australia. [2] Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
18
1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, Seattle, Washington, USA.

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.

Comment in

PMID:
25217958
PMCID:
PMC4177294
DOI:
10.1038/ng.3092
[Indexed for MEDLINE]
Free PMC Article

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