title: A copy number variation morbidity map of developmental delay.
abstract: 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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Tiffany H
authors.initials: TH
authors.lastname: Vu
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Charles
authors.initials: C
authors.lastname: Williams
authors.forename: Heather
authors.initials: H
authors.lastname: Stalker
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: Vickie
authors.initials: V
authors.lastname: Hannig
authors.forename: Hoda
authors.initials: H
authors.lastname: Abdel-Hamid
authors.forename: Patricia
authors.initials: P
authors.lastname: Bader
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCracken
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Niyazov
authors.forename: Kathleen
authors.initials: K
authors.lastname: Leppig
authors.forename: Heidi
authors.initials: H
authors.lastname: Thiese
authors.forename: Marybeth
authors.initials: M
authors.lastname: Hummel
authors.forename: Nora
authors.initials: N
authors.lastname: Alexander
authors.forename: Jerome
authors.initials: J
authors.lastname: Gorski
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kussmann
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.forename: Krys
authors.initials: K
authors.lastname: Johnson
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehder
authors.forename: Blake C
authors.initials: BC
authors.lastname: Ballif
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000328:Adult; D002675:Child, Preschool; D002874:Chromosome Mapping; D000013:Congenital Abnormalities / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D018628:Gene Dosage; D014644:Genetic Variation; D006801:Humans