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Published on: August 8, 2022
Exploring digenic inheritance in arrhythmogenic cardiomyopathy
Eva König1, Claudia Béu Volpato1, Benedetta Maria Motta1
1Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
Insights
This study investigated digenic inheritance in arrhythmogenic cardiomyopathy (ACM), identifying potential second genes that interact with PKP2 mutations. These findings may explain ACM
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Epidemiology
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder causing fibro-fatty tissue replacement in the heart muscle, leading to arrhythmias and sudden cardiac death.
- Despite being considered monogenic, ACM exhibits low penetrance, suggesting additional genetic or environmental factors influence disease development.
Purpose of the Study:
- To investigate digenic inheritance patterns in ACM families with known PKP2 mutations.
- To identify candidate genes that, in conjunction with PKP2 mutations, contribute to ACM pathogenesis.
Main Methods:
- Whole exome sequencing was employed in two ACM families.
- Candidate genes were identified by analyzing variants co-segregating with PKP2 mutations in affected versus healthy individuals.
- Computational prioritization focused on known ACM genes and those functionally related to PKP2.
Main Results:
- Four candidate genes (DAG1, DAB2IP, CTBP2, TCF25) were identified in family 1.
- Eleven candidate genes were found in family 2, with TTN being particularly promising due to rare deleterious variants in an affected individual.
- One TTN variant was located in the protein's serine kinase domain.
Conclusions:
- This study reports potential digenic contributors to ACM pathogenesis alongside PKP2 mutations.
- Further validation in larger cohorts is necessary to confirm the clinical utility of this digenic inheritance model for ACM.
Background:
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.
Methods:
We 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.
Results:
We 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.
Conclusions:
In 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.
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