Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by [≥]3 affected members. Across the sample, gene and gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship. In 14/16 families with [≥]3 affected individuals, we identified a total of 79 rare predicted deleterious variants in 79 unique genes shared by [≥]3 members with SMI and absent in 60 unrelated controls. Twenty (25%) genes were implicated in monogenic neurodevelopmental syndromes in OMIM, a fraction that is a significant overrepresentation (Fishers Exact test OR = 2.47, p = 0.001). In gene-set wise SKAT, statistically significant association was noted for genes related to synaptic function (SKAT-p = 0.014). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes.