Is the Phenotype–Genotype Relationship Necessary to Understand Cardiomyopathies?

Although the vast majority of genotyped patients with arrhythmogenic right ventricular dysplasia (ARVD)1,2,3 carry desmosomal gene mutations, with plakophilin 2 ( PKP2 ) being the most frequent,4 several nondesmosomal genes responsible for other cardiomyopathies/myopathies have been found that they can produce ARVD-like phenotypes, the so-called overlap syndromes.5–7 Phospholamban ( PLN ) is a transmembrane protein of the sarcoplasmic reticulum that plays a key role in calcium homeostasis a determinant of the force of cardiac contraction. PLN R14del, a founder gene mutation responsible for dilated cardiomyopathy (DCM),8,9 can produce ARVD-like phenotype as well.10,11 By conducting a multicenter study, van Rijsingen et al12 reported the clinical course of 403 mutation carriers from 83 families in this issue of the journal. Among 295 individuals with clinical information available, DCM phenotype is predominant, where 1% shows both DCM and ARVD and 6% with ARVD only. Among mutation carriers, no death or major cardiac events occurred before the age of 15 years. Symptomatic patients were older. Syncope, sustained, and nonsustained ventricular tachycardia, sudden cardiac death, and death caused …