Abstract
BackgroundArrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder, characterized by the substitution of heart muscle with fibro-fatty tissue and severe ventricular arrhythmias, often leading to heart failure and sudden cardiac death. ACM is considered a monogenic disorder, but the low penetrance of mutations identified in patients suggests the involvement of additional genetic or environmental factors.MethodsWe used whole exome sequencing to investigate digenic inheritance in two ACM families where previous diagnostic tests have revealed a PKP2 mutation in all affected and some healthy individuals. In family members with PKP2 mutations we determined all genes that harbor variants in affected but not in healthy carriers or vice versa. We computationally prioritized the most likely candidates, focusing on known ACM genes and genes related to PKP2 through protein interactions, functional relationships, or shared biological processes.ResultsWe identified four candidate genes in family 1, namely DAG1, DAB2IP, CTBP2 and TCF25, and eleven candidate genes in family 2. The most promising gene in the second family is TTN, a gene previously associated with ACM, in which the affected individual harbors two rare deleterious-predicted missense variants, one of which is located in the protein’s only serine kinase domain.ConclusionsIn this study we report genes that might act as digenic players in ACM pathogenesis, on the basis of co-segregation with PKP2 mutations. Validation in larger cohorts is still required to prove the utility of this model.
Highlights
Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder, characterized by the substitution of heart muscle with fibro-fatty tissue and severe ventricular arrhythmias, often leading to heart failure and sudden cardiac death
Rasmussen et al investigated 12 families with variants in DSG2. In three of these families, additional variants were identified in the DSP gene in affected family members. Individuals with both variants in DSG2 and DSP were affected by ACM, leading the authors to conclude that low penetrance of desomosmal variants in ACM patients may be explained by digenic inheritance [13]
Identification of candidate genes The filtering strategy described in the Methods Section and visualized in Fig. 2 resulted in 85 variants in 74 distinct genes in Family 1 (Fam1) and 242 variants in 212 distinct genes in Family 2 (Fam2)
Summary
Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder, characterized by the substitution of heart muscle with fibro-fatty tissue and severe ventricular arrhythmias, often leading to heart failure and sudden cardiac death. ACM is considered a monogenic disorder, but the low penetrance of mutations identified in patients suggests the involvement of additional genetic or environmental factors. Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder in which the ventricular myocardium is progressively replaced by fibro-fatty tissue. In three of these families, additional variants were identified in the DSP gene in affected family members Individuals with both variants in DSG2 and DSP were affected by ACM, leading the authors to conclude that low penetrance of desomosmal variants in ACM patients may be explained by digenic inheritance [13]. Non-genetic factors known to influence ACM penetrance are age, male sex and intense physical activity [16, 17]
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