Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease, affecting preferentially people under 40 years old with ventricular arrhythmia to sudden death. To date, the rate of successful genotyping is about 50%. Desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) are the most frequently mutated, the implication of the other genes associated with other cardiomyopathies is still debated. The pathogenicity of variants among these genes should be assessed not only based on the rarity because of the presence of rare variants in individuals in the general population.

Assess the pathogenicity of variants and the relevance of genes involved in ACM.

DNA from 179 patients with ACM were sequenced on a panel of 71 heart disease genes including 11 genes most often described in ACM. The pathogenicity of variants is assessed according to international guidelines (ACMG score) with 2 bioinformatic tools. We performed burden (CAST) and dispersion tests (SKAT, SKAT-O) on the 71 genes between patients and a control population.

Among the 179 patients, 34.6% have a pathogenic variant with PKP2 in 42 patients. Furthermore, 17.3% of patients have uncertain significance variants in genes involved in ACM. Burden tests showed a significant enrichment in pathogenic variants in PKP2, DSP, DSC2 and DSG2 (P<0.001) and in uncertain significance variants in the PKP2, DSG2 and DSC2 genes (P<0.01). No enrichment was observed among other genes. Patients with a variant in genes involved in ACM are diagnosed earlier than patients without variant (P<0.05).

Only desmosomal genes count a significate proportion of pathogenic variants in patients with ACM compared to control population. Uncertain significance variants in PKP2, DSC2, DSG2 genes seem to contribute to ACM and should be investigated. The age of symptom onset is correlated with the presence of pathogenic variant, thus justifying early family screening for better clinical management.