Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

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.

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

“…In ACM, loss of function due to NMD and triggered by PTC codon variants has been widely supported for all five desmosomal genes [ 9 , 21 , 26 , 27 , 28 , 29 ]. The position of a truncating mutation can govern the resulting phenotype, as mutations in the last exon can evade NMD [ 12 ].…”

The Double Mutation DSG2-p.S363X and TBX20-p.D278X Is Associated with Left Ventricular Non-Compaction Cardiomyopathy: Case Report

“…Loss of function mutations in DSG2 affect cardiomyocyte cohesion, force transduction, and calcium processing [27]. Of note, a large number of studies have shown an association of mutations in DSG2 and arrhythmogenic right ventricular cardiomyopathy (ARVC) [21,28,29]. However, other studies proved the relationship between the development of DCM and mutations in DSG2 [11,30].…”

Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

“…However, incomplete penetrance and variable expressivity ranging from mild phenotypes to severe cases including SCD are frequently observed even within the same family. In addition, de novo mutations and recessive, compound heterozygous, and digenetic inheritance can hide the genetic etiology in isolated index patients without familial history [18,19]. Currently, mutations in more than 25 different genes have been described (for an overview, see Fig.…”

“…Plakophilin-2 and plakoglobin bind to the cytoplasmic domains of desmoglein-2 (DSG2) and desmocollin-2 (DSC2), which are type I transmembrane proteins from the cadherin family. Hetero-and homo-or compound heterozygous pathogenic mutations in DSG2 and DSC2 have been described in about 5% of ACM patients [19,[32][33][34]. The majority of DSG2 and DSC2 mutations are localized in the extracellular domains, which consist of four cadherin and an anker domain, carrying several N-glycosylations and O-mannosylations [35,36].…”