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

2014-09-14

Coe, Bradley P

Witherspoon, Kali

Rosenfeld, Jill A

van Bon, Bregje W M

Vulto-van Silfhout, Anneke T

Bosco, Paolo

Friend, Kathryn L

Baker, Carl

Buono, Serafino

Vissers, Lisenka E L M

Schuurs-Hoeijmakers, Janneke H

Hoischen, Alex

Pfundt, Rolph

Krumm, Nik

Carvill, Gemma L

Li, Deana

Amaral, David

Brown, Natasha

Lockhart, Paul J

Scheffer, Ingrid E

Alberti, Antonino

Shaw, Marie

Pettinato, Rosa

Tervo, Raymond

de Leeuw, Nicole

Reijnders, Margot R F

Torchia, Beth S

Peeters, Hilde

O'Roak, Brian J

Fichera, Marco

Hehir-Kwa, Jayne Y

Shendure, Jay

Mefford, Heather C

Haan, Eric

Gécz, Jozef

de Vries, Bert B A

Romano, Corrado

Eichler, Evan E

Journal Article

10.1038/ng.3092

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.

link

Nature Genetics 2014; 46(10): 1063-71

Nature genetics