Journal Article

Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients

Mushtaq, Saima, Sommariva, Elena, Pompilio, Giulio, Lippi, Melania, Di Blasio, Anna Maria, Casella, Michela, Biondi, Maria Luisa, Novelli, Valeria, Pedrazzini, Matteo, Rovina, Davide, Chiesa, Mattia, Ascione, Ciro, Colombo, Gualtiero I., Riggio, Daniela

2022

Overview

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-phenotype associations between common variants and clinical parameters. Arrhythmia-associated polymorphisms resulted in an increased risk of arrhythmic events during patients’ follow-up. The description of the genetic framework of our population and the observed genotype-phenotype correlation constitutes the starting point to address the current lack of knowledge in the genetics of ACM.

• Publisher: MDPI AG,MDPI
• Subject: Ablation / Analysis / Arrhythmia / arrhythmogenic cardiomyopathy / Biopsy / Cardiac arrhythmia / Cardiomyopathy / Cardiovascular disease / Cardiovascular diseases / cardiovascular genetics / Care and treatment / Catheters / common variants / Coronary vessels / desmosomal genes / Diabetes / Diagnosis / DNA sequencing / Electrocardiography / Family medical history / Genetic aspects / Genetic diversity / Genetic variation / Genomes / Genomics / Genotype & phenotype / genotype-phenotype correlation / Heart diseases / Hypertension / Mutation / Next-generation sequencing / Nucleotide sequencing / Pathogenicity / Patients / Phenotypes / Population genetics / rare variants / Survival analysis / Task forces / Variables / Vein & artery diseases