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

Abstract

IntroductionWhole Exome Sequencing (WES) studies have provided important insights into the genetic architecture of neuropsychiatric syndromes identifying rare and novel variants in the protein-coding sequence of the genome that impact function. Variants and genes that are central to the shared biology of these clinical syndromes may be identified by WES in families with multiple affected individuals with serious mental illnesses (F-SMI).MethodsWe performed WES in 250 individuals (affected = 186, family-control = 64) from 100 families, each with ≥2 members with SMI, and 60 unrelated population-controls. Within pedigree prioritization employed criteria of 1. rarity (Minor Allele Frequency <0.1%, GnomAD South-Asian sample, 15308 exomes); 2. functional consequence (‘Loss of Function’ or ‘missense deleterious in 4/5 in silico predictions). 3. sharing by ≥3 affected members within a family. Across the sample, gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship.ResultsIn 17 families with ≥3 exome samples, we identified 79 rare predicted deleterious variants in 79 unique genes shared by ≥3 affected members and absent in 60 unrelated controls. Twenty (25.32%) genes were implicated in monogenic neurodevelopmental syndromes in Online Mendelian Inheritance in Man representing a statistically significant overrepresentation (Fisher’s 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 = 0.017).DiscussionIn F-SMI based WES study, we identify private, rare, protein altering variants in genes previously implicated in monogenic Mendelian neuropsychiatric syndromes; suggesting pleotropic influences in neurodevelopment between complex and monogenic syndromes.