Richard NW Hauer
Netherlands Heart Institute, Netherlands
Title: Genotype-phenotype correlation in arrhythmogenic cardiomyopathies
Biography
Biography: Richard NW Hauer
Abstract
Introduction: Arrhythmogenic Cardiomyopathies (ACM) are inherited cardiomyopathies histologically caracterized by fibro-fatty myocardial alteration, and clinically by ventricular arrhythmias starting at an early disease stage, usually later followed by identifiable structural and hemodynamic disorder. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is in its typical form a subcategory of ACM with primarily RV involvement. However, ACM also includes predominant left ventricular disease. ACM is associated with pathogenic mutations encoding desmosomal and non-desmosomal proteins.
Aim: Analysis of genotype-phenotype correlation in a large transatlantic ACM patient cohort.
Results: In 577 well-phenotyped patients (230 probands, 347 relatives) pathogenic mutations were found in 5 desmosomal (JUP, PKP2, DSG2, DSC2, DSP) and 2 non-desmosomal genes (TMEM43, PLN). Mutations in PKP2 were found in 80% of individuals. 36 Patients presented with sudden cardiac death, particularly in 4/19 (21%) with DSP, versus only 29/463 (6%) with PKP2.Those presenting alive were followed during 6±7 years. Arrhythmic outcome in males was worse compared to females, and >1 mutation did worse compared to a single mutation. PLN and DSP were significantly more associated with left ventricular dysfunction than PKP2. Premature truncating, splice site, and missense mutations were associated with a similar arrhythmic and hemodynamic outcome.
Conclusion: Genotype-phenotype correlation shows clinically relevant differences. Because of frequent predominant left ventricular involvement in DSP and PLN, fulfilment of ARVD/C Task Force Criteria may be absent, although these subcategories have an unfavorable outcome.