Refining analyses of copy number variation identifies specific genes associated with developmental delay : Nature Genetics : Nature Publishing Group

Refining analyses of copy number variation identifies specific genes associated with developmental delay : Nature Genetics : Nature Publishing Group

Birth Defects & Child Health

Refining analyses of copy number variation identifies specific genes associated with developmental delay. 
Bradley P Coe et al. Nature Genetics, September 14, 2014

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
• et al.

• Affiliations
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• Corresponding author

Nature Genetics

 

(2014)

 

doi:10.1038/ng.3092

Received

 

11 April 2014 

Accepted

 

20 August 2014 

Published online

 

14 September 2014

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Abstract

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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.