Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young.

Abstract

Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death. Here we report aclinical investigation and an extensive genetic assessment of aTunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify6 ultra-rare pathogenic heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes, and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV consistent with the family phenotype. Overall, our results are highly suggestive for acumulative effect of heterozygous missense variants as disease causation and to account for agreater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES and segregation analysis in the identification of family specific mutations within different cardiac genes pathways.