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Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death.

ABSTRACT: Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these diseases can range from asymptomatic to syncope but sudden death can sometimes be the first symptom of disease. Early identification of at-risk individuals is crucial to prevent a lethal episode. In this review, we will focus on the genetic basis of channelopathies and the effect of genetic and non-genetic modifiers on their phenotypes.

SUBMITTER: Coll M

PROVIDER: S-EPMC5872029 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death.

Coll Monica M Pérez-Serra Alexandra A Mates Jesus J Del Olmo Bernat B Puigmulé Marta M Fernandez-Falgueras Anna A Iglesias Anna A Picó Ferran F Lopez Laura L Brugada Ramon R Campuzano Oscar O

Biology 20171226 1

Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these d ...[more]

PMID: 29278359

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Project description:BackgroundThere is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features.MethodsUK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative.ResultsAmong 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes.ConclusionsIn the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Dataset Information

Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death.

Publications

Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death.

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