Case report: Additional variants induced sudden cardiac death among pediatric ACM with DSG2 homozygous mutant genotype: a report of three cases
Abstract
Background: Mutations in genes encoding desmosomal proteins are the leading cause of arrhythmogenic cardiomyopathy (ACM). The majority of the inherited ACM cases demonstrate autosomal dominant genotype. Several cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype demonstrate adverse clinical outcomes, but the roles of associated genetic mutations are not clear. In this report, we describe three ACM cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype combined with additional heterozygous cardiomyopathy-related genetic mutations that cause aggravated clinical manifestations and worse clinical outcomes.
Case presentation: The three reported probands demonstrated similar clinical presentations such as heart failure, cardiac enlargement, and lethal arrhythmias. All of them experienced sudden cardiac death (SCD) before undergoing implantable cardioverter defibrillator (ICD) or heart transplantations. Whole-exome sequencing analysis demonstrated that the three patients inherited the homozygous DSG2 c.1592T>G (p.F531C) variant. Furthermore, probands I, II, and III also inherited additional heterozygous cardiomyopathy-associated mutations, including DSP c.7883T>C, SCN5a c.3577C>T, or MYH7 c.427C>T, respectively. These variants were confirmed as pathogenetic variants. A systematic review of all the reported ACM cases with the homozygous DSG2 variants suggested that the additional genetic mutations contributed to the early age onset of ACM and lethal…
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