Abstract 469: Genomic Context Predicts Dilated but Not Hypertrophic Cardiomyopathy

Abstract

Rationale: Cardiomyopathies are a major cause of heart failure and have a strong heritable component. Objective: Determine the role of both common and rare nonsynonymous genetic variation in hypertrophic (HCM) and dilated familial cardiomyopathy (DCM). Methods and Results: Whole genome sequencing was used to determine common and rare nonsynonymous genetic variation in familial cases of HCM (n=56) or DCM (n=71). Variation was evaluated in 102 cardiomyopathy genes routinely assayed in clinical and commercial gene testing panels. We used cardiac gene expression data from GTEx (Genotype-Tissue Expression database) to define additional genes expressed in the heart. The number of nonsynonymous single nucleotide variants (nsSNVs), the majority of which were missense variants, was correlated with echocardiographic measurements. Principal component analysis (PCA) of left ventricular measures separated HCM and DCM. Regression of the first principal component using all nonsynonymous single nucleotide variants (nsSNVs) in cardiomyopathy genes showed the number of nsSNVs predicted DCM but not HCM. DCM probability in the cohort significantly increased as the number of cardiomyopathy gene nsSNVs increased (p<0.02). The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter in DCM. Resampling methods identified genes with deviant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions: DCM subjects carry a greater burden of nsSNVs in cardiomyopathy genes. This genomic burden translates to impaired systolic cardiac function in DCM. In contrast, nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support a complex inheritance for DCM where increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity. The distinct genetic landscapes of HCM and DCM suggest that greater genetic variation in cardiac genes provokes unfavorable ventricular remodeling with reduced systolic function.