부산대학교 도서관

Loss of function variants in PKP2 are associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), but little is known about the consequences of PKP2 missense variation. We hypothesized that truncating variants in PKP2 are more likely to be associated with cardiomyopathy than missense, and that the pathogenicity of PKP2 missense variants varies by gene region. We assembled genetic tests from probands with variants in PKP2 and ARVC-relevant diagnoses from industry partners (N=176) and evaluated the proportion of probands with truncating (N=98) and missense (N=78) variants in this disease-associated population vs. the general population (represented by gnomAD: N=97 truncating; N=12408 missense). Truncating variants were enriched in the disease-associated population (OR=160.7, p<0.0001), while missense variants were not. To identify potential hotspots for pathogenic missense variation, we examined the proportion of probands with disease-associated vs. general population-associated missense variants within sliding windows across the length of the PKP2 transcript. We found 18 windows enriched for diseased probands with missense variants, one of which lies within a known functional domain (FDR=0.001, Figure 1). We then performed a variant-level analysis on independent publicly available databases of ARVC-associated variants (University Medical Center Groningen and ClinVar, N=44 vs. gnomAD, N=546), and found two of the same windows (FDR=0.2). Four out of six PKP2 missense variants listed as pathogenic in ClinVar fell within disease-associated windows. Truncating PKP2 variants are more likely to be associated with disease than missense variants. Examination of disease-associated regions of missense variation in PKP2 identified potential hotspots for pathogenicity. Future directions include further validation based on highly clinically adjudicated ARVC populations and in vitro examination of functional relevance of these domains.