A Copy Number Variation (CNV) Morbidity Map of Developmental Delay This study presents a comprehensive analysis of copy number variations (CNVs) in 15,767 children with intellectual disability (ID) and developmental delay (DD), compared to 8,329 adult controls. The research estimates that approximately 14.2% of disease in these individuals is due to large CNVs greater than 400 kbp. The study finds that patients with craniofacial anomalies and cardiovascular defects have greater CNV enrichment than those with epilepsy or autism. The researchers identified 59 pathogenic CNVs, including 14 novel or previously weakly supported candidates. They refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. The study also developed methods to discover small, disruptive CNVs within large diagnostic array datasets. The study reveals striking differences in the CNV landscape, including potentially pathogenic genes, refinement of known disease-causing mutations, and the discovery of potentially novel genes. The CNV burden was significantly higher in cases with more severe developmental phenotypes associated with multiple congenital abnormalities. For example, children with craniofacial and cardiovascular defects showed a significantly increased burden of large CNVs compared to those with autism spectrum disorder. The study also identified locus-specific enrichments, with 27.5% of enriched CNV-loci residing at genomic hotspots flanked by large blocks of highly similar segmental duplications. The researchers identified a 660 kbp deletion on chromosome 15q25.2, which is associated with developmental delay and learning disability. They also found that the 15q11.2 deletion is significantly enriched, although at lower penetrance than most other genomic disorders. The study analyzed gene content and identified 615 genes significantly deleted in any phenotype, with the majority associated with known pathogenic loci or subtelomeric alterations. The researchers also identified 325 duplicated genes significantly enriched among patients. These findings suggest that these genes may play a role in the phenotypic consequences of larger CNVs. The study also discovered smaller gene-disrupting CNVs, including deletions in the PARK2 gene and TBX5 gene, which are associated with various neurological and developmental disorders. The researchers found that these CNVs may contribute to the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders. The study highlights the importance of CNV analysis in understanding the genetic basis of developmental delay and other neurological disorders. The findings suggest that CNVs play a significant role in these conditions and that further research is needed to fully understand their impact. The study provides a valuable resource for clinicians and researchers in the diagnosis and treatment of these conditions.A Copy Number Variation (CNV) Morbidity Map of Developmental Delay This study presents a comprehensive analysis of copy number variations (CNVs) in 15,767 children with intellectual disability (ID) and developmental delay (DD), compared to 8,329 adult controls. The research estimates that approximately 14.2% of disease in these individuals is due to large CNVs greater than 400 kbp. The study finds that patients with craniofacial anomalies and cardiovascular defects have greater CNV enrichment than those with epilepsy or autism. The researchers identified 59 pathogenic CNVs, including 14 novel or previously weakly supported candidates. They refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. The study also developed methods to discover small, disruptive CNVs within large diagnostic array datasets. The study reveals striking differences in the CNV landscape, including potentially pathogenic genes, refinement of known disease-causing mutations, and the discovery of potentially novel genes. The CNV burden was significantly higher in cases with more severe developmental phenotypes associated with multiple congenital abnormalities. For example, children with craniofacial and cardiovascular defects showed a significantly increased burden of large CNVs compared to those with autism spectrum disorder. The study also identified locus-specific enrichments, with 27.5% of enriched CNV-loci residing at genomic hotspots flanked by large blocks of highly similar segmental duplications. The researchers identified a 660 kbp deletion on chromosome 15q25.2, which is associated with developmental delay and learning disability. They also found that the 15q11.2 deletion is significantly enriched, although at lower penetrance than most other genomic disorders. The study analyzed gene content and identified 615 genes significantly deleted in any phenotype, with the majority associated with known pathogenic loci or subtelomeric alterations. The researchers also identified 325 duplicated genes significantly enriched among patients. These findings suggest that these genes may play a role in the phenotypic consequences of larger CNVs. The study also discovered smaller gene-disrupting CNVs, including deletions in the PARK2 gene and TBX5 gene, which are associated with various neurological and developmental disorders. The researchers found that these CNVs may contribute to the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders. The study highlights the importance of CNV analysis in understanding the genetic basis of developmental delay and other neurological disorders. The findings suggest that CNVs play a significant role in these conditions and that further research is needed to fully understand their impact. The study provides a valuable resource for clinicians and researchers in the diagnosis and treatment of these conditions.