Shared Desmosome Gene Findings in Early and Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

摘要

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited form of cardiomyopathy with low penetrance and variable expressivity. Dominant mutations and rare polymorphisms in desmosome genes are frequently identified. We reasoned that individuals with earlier onset disease would have more frequent desmosome gene mutations and rare polymorphisms. Three groups were compared: Young with symptoms attributable to ARVD/C or a diagnosis of ARVD/C at age of 21 years or earlier, Middle with first symptoms or diagnosis age of 22–49 years, and Late with first symptoms or diagnosis at age of 50 or more years. deoxyribonucleic acid (DNA) sequence analysis was performed on five cardiac desmosome genes, and the presence of mutations and rare missense polymorphisms was compared among the three groups. In the entire Young cohort, 20 (67%) had one or more cardiac desmosome gene mutations. The prevalence of cardiac desmosome gene mutations was similar in the Middle (48%) and Late (53%) cohorts (P = 0.23). Similar numbers of individuals in each cohort had more than one desmosome gene mutation, although the numbers are too small for statistical comparisons. The prevalence of certain rare missense DNA variants was not different among the cohorts (P = 0.71), yet these rare missense alleles were more prevalent in the overall study cohort of 112 ARVD/C participants compared to 100 race-matched controls (P = 0.027). The presence of these variants did not associate with the age of onset of ARVD/C or ventricular tachycardia. These findings highlight the complex interplay of environmental and genetic factors contributing to this condition.