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Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.

ABSTRACT: Mutations in genes encoding ion channel pore-forming ?-subunits and accessory ?-subunits as well as intracellular calcium-handling proteins that collectively maintain the electromechanical function of the human heart serve as the underlying pathogenic substrate for a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similar to many Mendelian disorders, the cardiac "channelopathies" exhibit incomplete penetrance, variable expressivity, and phenotypic overlap, whereby genotype-positive individuals within the same genetic lineage assume vastly different clinical courses as objectively assessed by phenotypic features such electrocardiographic abnormalities and number/type of cardiac events. In this Review, we summarize the current understanding of the global architecture of complex electrocardiographic traits such as the QT interval, focusing on the role of common genetic variants in the modulation of ECG parameters in health and the environmental and genetic determinants of incomplete penetrance and variable expressivity in the heritable cardiac arrhythmia syndromes most likely to be encountered in clinical practice.

SUBMITTER: Giudicessi JR

PROVIDER: S-EPMC3624763 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.

Giudicessi John R JR Ackerman Michael J MJ

Translational research : the journal of laboratory and clinical medicine 20120917 1

Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain the electromechanical function of the human heart serve as the underlying pathogenic substrate for a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycard ...[more]

PMID: 22995932

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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

Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.

Publications

Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes.

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