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Genetic Aspects of Arrhythmogenic Right Ventricular Cardiomyopathy

Alex HÝrby Christensen


Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease of the cardiomyocyte. The disease is characterized by fibrofatty infiltrations in the myocardium, right- and/or left ventricular involvement, and ventricular tachyarrhythmias. ARVC is diagnosed as a syndrome based on published criteria. The disease is typically inherited as an autosomal dominant disorder and has been associated with mutations in genes encoding cellular adhesion proteins.
The aims of this thesis were to expand the existing knowledge on the molecular genetic background of ARVC. For this purpose a patient cohort consisting of 65 unrelated patients with ARVC or ARVC-like disease was recruited. We performed a comprehensive screening of all known desmosomal genes, screened the genes TGFb3 and TMEM43, evaluated the contribution of large genomic rearrangements, and screened three novel candidate genes. In addition, we wished to correlate our clinical and genetic findings. The results are presented in four manuscripts: The first manuscript critically evaluates the prevalence of mutations in the gene plakophilin-2 in a Danish ARVC cohort. Fifteen percent of patients carried potentially disease-causing mutations in the gene. Our data furthermore suggested that some genetic variants were disease-modifying but not directly diseasecausing. The second manuscript reports the result of screening of five additional genes (DSC2, DSG2, DSP, JUP, and TGFb3) and evaluation of large genomic rearrangements. Combined with the plakophilin-2 screening, 33% of the studied patients had identifiable point mutations with a surprisingly wide mutation spectrum. No genomic rearrangements were found. A substantial proportion of patients carried more than one mutation. The phenotype associated with the double mutation carrier status was variable. A single patient carried a homozygous mutation in the desmoplakin gene consistent with a Carvajal-like syndrome. The third manuscript describes the screening of the gene TMEM43, which has been associated with a distinct form of ARVC characterized by full penetrance and a lethal clinical course. Mutations were found in two families. We furthermore characterized the  immunohistochemical features associated with the mutations.
The fourth manuscript reports the screening of three novel candidate genes. Three genes (alpha-Tcatenin, beta-catenin, and PERP), involved in cellular adhesion and expressed at the intercalated disc in the human heart, were evaluated. No disease-causing mutations were found consistent with that these genes are not common causes of ARVC. In conclusion, 36% of ARVC patients in this Danish cohort had identifiable mutations with a wide mutation spectrum. The molecular genetic background of ARVC is complex, double mutation carriers are not rare, large phenotypic variation is seen, and assessment of pathogeneity is challenging. Genetic diagnostics has the potential to aid the diagnostic process, improve risk stratification, and optimize treatment of patients and their families.