Examining the size distribution of CNVs in the context of major subphenotypes shows that the large CNV burden is increased in more severe developmental phenotypes associated with multiple congenital abnormalities. We find, for example, that children also diagnosed with craniofacial and cardiovascular defects show a significantly increased burden of large CNVs when compared to children with autism spectrum disorder (p = 4.99×10−10 and 6.45×10−5, respectively, at >400 kbp) (Figure 1B). Children with an additional diagnosis of epilepsy/severe seizure disorder tend to have a more intermediate CNV burden when compared to individuals with autism or more severe ID (Supplementary Figure 2). These distinctions remain significant even after excluding CNVs larger than 10 Mbp (which would have been detectable by karyotype analysis) and when the CNV burden among the subset of controls screened for psychiatric disease is used as the baseline, demonstrating a role for large CNVs in more severe phenotypic variation.
