We present one of the largest studies investigating the role of rare CNVs in ID and DD, analyzing data from 15,767 affected individuals and 8,329 controls. These data quantify the massive contribution of large CNVs to pediatric disease, with 25.7% of affected individuals harboring CNVs >400 kbp in contrast with only 11.5% of controls. Disease risk increases steadily in relation to CNV size, with an odds ratio >20 for carriers of CNVs larger than 1.5 Mbp and nearly 50 at a threshold of 3 Mbp. We find that the CNV burden differs significantly depending on the nature of the primary clinical referral, with craniofacial abnormalities and structural defects of the heart being especially enriched for large CNVs relative to epilepsy and autism spectrum disorder (Figure 1, Supplementary Figure 2). As has been observed in model organisms and predicted based on theory47,48, haploinsufficiency appears more common and penetrant than triplosensitivity for severe developmental phenotypes. While this cohort does not represent a random sampling of individuals with ID/DD and includes some individuals without ID or DD, our estimates are likely applicable to
