Journal Article

A copy number variation morbidity map of developmental delay

Alexander, Nora, Hummel, Marybeth, Hamid, Rizwan, Williams, Charles, Niyazov, Dmitriy, Shaffer, Lisa G, Cooper, Gregory M, Rehder, Catherine, Eichler, Evan E, Stalker, Heather, Thiese, Heidi, Girirajan, Santhosh, Kussmann, Jennifer, Coe, Bradley P, Shashi, Vandana, Leppig, Kathleen, Bader, Patricia, Rosenfeld, Jill A, McCracken, Elizabeth, Hannig, Vickie, Ballif, Blake C, Abdel-Hamid, Hoda, Vu, Tiffany H, Johnson, Krys, Baker, Carl, Gorski, Jerome

2011

Overview

Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, developmental delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs. To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/1647/1513/1382 / 631/208/2489/144 / 692/700/1720 / Adult / Agriculture / Animal Genetics and Genomics / Autism / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Birth defects / Cancer Research / Child, Preschool / Chromosome Mapping / Congenital Abnormalities - genetics / Congenital defects / Data collection / Developmental Disabilities - genetics / Diagnosis / Disability / Disease / Fundamental and applied biological sciences. Psychology / Gene Dosage / Gene expression / Gene Function / Genetic aspects / Genetic Variation / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Heterogeneity / Human Genetics / Humans / Medical research / Morbidity / Mutation / Pediatrics / Womens health