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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2017

Open Access 01-12-2017 | Research article

Exploring digenic inheritance in arrhythmogenic cardiomyopathy

Authors: Eva König, Claudia Béu Volpato, Benedetta Maria Motta, Hagen Blankenburg, Anne Picard, Peter Pramstaller, Michela Casella, Werner Rauhe, Giulio Pompilio, Viviana Meraviglia, Francisco S. Domingues, Elena Sommariva, Alessandra Rossini

Published in: BMC Medical Genetics | Issue 1/2017

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Abstract

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.
Appendix
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Metadata
Title
Exploring digenic inheritance in arrhythmogenic cardiomyopathy
Authors
Eva König
Claudia Béu Volpato
Benedetta Maria Motta
Hagen Blankenburg
Anne Picard
Peter Pramstaller
Michela Casella
Werner Rauhe
Giulio Pompilio
Viviana Meraviglia
Francisco S. Domingues
Elena Sommariva
Alessandra Rossini
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2017
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-017-0503-7

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