Exploring digenic inheritance in arrhythmogenic cardiomyopathy

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...

Full description

Saved in:
Bibliographic Details
Published in:BMC medical genetics Vol. 18; no. 1; pp. 145 - 12
Main Authors: König, Eva, Volpato, Claudia Béu, Motta, Benedetta Maria, Blankenburg, Hagen, Picard, Anne, Pramstaller, Peter, Casella, Michela, Rauhe, Werner, Pompilio, Giulio, Meraviglia, Viviana, Domingues, Francisco S., Sommariva, Elena, Rossini, Alessandra
Format: Journal Article
Language:English
Published: London BioMed Central 08.12.2017
BioMed Central Ltd
BMC
Subjects:
ACM
Arrhythmia
Arrhythmogenic cardiomyopathy
Biomedical and Life Sciences
Biomedicine
Cardiomyopathy
Clinical-Molecular Genetics and Cytogenetics
Complications and side effects
Cytogenetics
Digenic inheritance
Exome sequencing
Gene Function
Genetic aspects
Genetic susceptibility
Heart diseases
Human Genetics
Physiological aspects
PKP2
Research Article
Risk factors
Italy
Digenic inheritance
PKP2
Arrhythmogenic cardiomyopathy
ACM
Exome sequencing
ISSN:1471-2350, 1471-2350
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1471-2350
1471-2350
DOI:10.1186/s12881-017-0503-7