Refining analyses of copy number variation identifiesspecific genes associated with developmental delay

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically
large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children
with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26
candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of
CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset
of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated
CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive
language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features.

This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric
disease despite extensive genetic heterogeneity.