Unraveling Missing Genes and Missing Inheritance in Arrhythmogenic Cardiomyopathy
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See Article by Pilichou et al
Arrhythmogenic cardiomyopathy (AC) is an enigmatic inherited cardiomyopathy characterized by fibro-fatty replacement of cardiac myocytes and ventricular arrhythmias.1–3 When affecting predominantly the right ventricle, this disease is referred as arrhythmogenic right ventricular cardiomyopathy. The prevalence of AC in the general population has been estimated in a range from 1 in 2000 to 1 in 5000 individuals. Clinically, it is characterized by palpitations, syncope, and sudden cardiac death because of ventricular arrhythmias. This cardiomyopathy is a major cause of sudden cardiac death in the young people and in athletes.1–3 To date, there is no effective pharmacological therapy for this deadly cardiac disease, which may require implantable defibrillators and heart transplantation at the advanced stage.4
AC is a hereditary autosomal dominant disease with reduced penetrance and variable clinical expression. Thus far, 5 causal genes have been identified, all coding for desmosomal proteins.5 These known causal desmosomal genes are plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and democollin-2 (DSC2). Desmosomal proteins are structural proteins important for cell–cell attachment and communication. PKP2 is the most common causal gene for AC, accounting for up to 43% of the cases.6–8 Most of PKP2 mutations are loss-of-function mutations resulting in reduced expression of PKP2 (haploinsufficiency6,9). Atypical forms of AC are caused by mutations in nondesmosomal genes, such as transforming growth factor-β-3 (TGFβ3), cardiac ryanodine receptor (RYR2), transmembrane protein 43 (TMEM43), and lamin A/C (LMNA). Current diagnostic strategies rely on next-generation DNA sequencing that has poor sensitivity for genomic deletions and identifies causative variants in only ≈50% of the AC cases, leaving half of cases with unknown genetic cause. To address …