Abstract
About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.
Highlights
Desmosomes are multiple protein complexes mediating the cell–cell adhesion of cardiomyocytes and epithelial cells [1]
Results of arrhythmogenic right ventricular cardiomyopathy (ARVC) according to the revised task force criteria [27]
No further family members were clinically affected, we performed a genetic analysis of the affected index patient using a broad next-generation sequencing (NGS) panel, covering 174 genes associated with cardiomyopathies or syndromes with cardiac involvement
Summary
Desmosomes are multiple protein complexes mediating the cell–cell adhesion of cardiomyocytes and epithelial cells [1]. The cadherins desmoglein-2 and desmocollin-2 (encoded by DSG2 and DSC2) are type I transmembrane glycoproteins [2,3,4] and mediate the calcium-dependent cell–cell adhesion between cardiomyocytes. Both proteins have extracellular domains consisting of four cadherin domains (EC1–4) and an anchor domain (EA) [5]. Mutations in the cardiac desmosomal genes and in addition in DES cause arrhythmogenic cardiomyopathy (ACM, MIM, #609040) [11,12,13,14,15,16,17]. Because no further family members were clinically affected, we suggest a recessive inheritance in both cases
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