This study investigates the genetic heterogeneity underlying developmental delay by comparing copy-number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects to 8,329 adult controls. The researchers estimate that approximately 14.2% of the disease in these individuals is due to large CNVs >400 kbp. They find greater CNV enrichment in patients with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. The study identifies 59 pathogenic CNVs, including 14 novel or weakly supported candidates, and refines the critical intervals for several genomic disorders such as the 17q21.31 microdeletion syndrome. Additionally, they develop methods to discover small, disruptive CNVs within large diagnostic datasets. The CNV morbidity map, combined with exome/genome sequencing, will be crucial for understanding the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders.This study investigates the genetic heterogeneity underlying developmental delay by comparing copy-number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects to 8,329 adult controls. The researchers estimate that approximately 14.2% of the disease in these individuals is due to large CNVs >400 kbp. They find greater CNV enrichment in patients with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. The study identifies 59 pathogenic CNVs, including 14 novel or weakly supported candidates, and refines the critical intervals for several genomic disorders such as the 17q21.31 microdeletion syndrome. Additionally, they develop methods to discover small, disruptive CNVs within large diagnostic datasets. The CNV morbidity map, combined with exome/genome sequencing, will be crucial for understanding the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders.