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

John R. Giudicessi, Michael J. Ackerman

Research output: Contribution to journalReview article

75 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalTranslational Research
Volume161
Issue number1
DOIs
StatePublished - Jan 2013

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ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

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