Compound and Digenic Heterozygosity in Desmosome Genes as a Cause of Arrhythmogenic Right Ventricular Cardiomyopathy in Japanese Patients

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder mostly caused by desmosome gene mutations. Recent comprehensive desmosome mutation analyses of Caucasian ARVC patients have revealed the presence of not only a single heterozygous mutation, but also compound and digenic heterozygosity. However, the genetic basis of Japanese ARVC remains poorly elucidated. Methods and Results: The subjects were 7 definite and 1 possible ARVC probands (6 males, 16-76 years of age), and their family members. Genetic screening for major ARVC-causing genes (junction plakoglobin, desmoplakin, plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2) was performed. We identified 3 cases of compound heterozygosities (Case 1: DSG2 S194L and DSG2 R292C; Case 2: PKP2 2489+1G>A and PKP2 D812N; Case 3: PKP2 M565R and PKP2 D812N) and 1 of digenic heterozygosity (Case 4: PKP2 1728_1729insGATG and DSG2 R292C) among the definite ARVC patients. All family members we investigated have remained asymptomatic. They carried, if any, only a single variant, indicating that the probands carry in trans compound heterozygosity. These results suggest that each of these variants alone may not be sufficient and second variants may be required to manifest overt ARVC in Japanese patients. Conclusions: Our comprehensive genetic analysis of desmosome genes identified 3 cases of compound heterozygosities in trans and 1 of digenic heterozygosity among 7 definite Japanese ARVC patients, providing novel insights into the genetic basis of Japanese ARVC. (Circ J 2012; 76: 737-743)