Abstract
Background: Dilated cardiomyopathy (DCM) has been associated with hundreds of genetic variants across 62 genes. These associations are now being questioned by large control populations in which these variants are found with high allele frequencies. Hypothesis: We hypothesized that genetic variants previously associated with DCM are overrepresented in the population-based ExAC database when taking the prevalence of the disease into account. Hence, we aimed to identify potentially false-positive variants previously associated with DCM. Methods: We identified all previously DCM associated variants in The Human Gene Mutation Database (HGMD). We then systematically searched for these in the ExAC database containing exome data on 61.000 individuals. In addition, we performed a PolyPhen-2 prediction on all variants, including those not found in the ExAC database. Results: We identified 148 (31%) out of 473 variants previously associated with DCM in ExAC. These variants included eight stop-gain variants, eight splice variants and 132 missense variants. The 148 variants affected 7.928 alleles corresponding to a genotype prevalence of 1:7 in the ExAC population. Thirty-five variants were found in 25 or more alleles, corresponding to a DCM genotype prevalence of 1:8 Furthermore, we identified all variants previously associated with DCM in 14 genes; hereof 4 genes only contained variants above our estimated allele frequency (25:61000). Polyphen-2 analysis predicted 53 (36%) variants to be benign in the ExAC population compared with 53 (16%) among variants not found in ExAC (p<0.001). Conclusion: In conclusion, we identified much higher genotype prevalence of previously DCM associated variants than expected in the exome data from ExAC. More importantly we found 4 genes in which all previously identified variants were found with relative high allele frequencies, questioning the association of these genes with the monogenic form of DCM.
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