Journal Article

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

Romano, Corrado, Lockhart, Paul J, Shendure, Jay, de Leeuw, Nicole, Alberti, Antonino, Gécz, Jozef, Vissers, Lisenka E L M, Pettinato, Rosa, Schuurs-Hoeijmakers, Janneke H, van Bon, Bregje W M, Thompson, Elizabeth, Eichler, Evan E, Pfundt, Rolph, Scheffer, Ingrid E, Krumm, Nik, Reijnders, Margot R F, Li, Deana, Buono, Serafino, O'Roak, Brian J, Hoischen, Alex, Carvill, Gemma L, Mefford, Heather C, de Vries, Bert B A, Friend, Kathryn L, Coe, Bradley P, Tervo, Raymond, Vulto-van Silfhout, Anneke T, Haan, Eric, Rosenfeld, Jill A, Peeters, Hilde, Fichera, Marco, Witherspoon, Kali, Amaral, David, Brown, Natasha, Bosco, Paolo, Shaw, Marie, Torchia, Beth S, Baker, Carl, Hehir-Kwa, Jayne Y

2014

Overview

Evan Eichler and colleagues report an expanded copy number variation (CNV) morbidity map of developmental delay, with additional resequencing of candidate genes in regions implicated by large CNVs. They identify several new disease-associated CNVs and show how their combined approach facilitates discovery of new developmental syndromes and disease genes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 45/61 / 631/208/1516 / 631/208/212 / 692/699/375/366 / Agriculture / Animal Genetics and Genomics / Autism / Autistic Disorder - genetics / Base Sequence / Biomedicine / Cancer Research / Carrier Proteins - genetics / Cell Cycle Proteins / Child / Chromosome Mapping / Co-Repressor Proteins / Comparative Genomic Hybridization / Copy number variations / Developmental delay / Developmental Disabilities - genetics / DNA Copy Number Variations / DNA-Binding Proteins / Female / Gene Function / Genes / Genetic aspects / Genetic Association Studies / Genetic Predisposition to Disease - genetics / Genomics / Haploinsufficiency - genetics / Health aspects / Heterogeneity / Human Genetics / Humans / Identification and classification / Integrated approach / Intellectual Disability - genetics / Male / Medical research / Mental health / Molecular Sequence Data / Morbidity / Mutation / Nuclear Proteins - genetics / Polymorphism, Single Nucleotide / Psychological aspects / Sequence Analysis, DNA / Studies