Featured New InvestigatorDeterminants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes
Section snippets
Electromechanical Activity of the Heart in Health and Disease
In healthy individuals, the spontaneous depolarization of specialized “pacemaker” cells within the sinoatrial node of the right atrium initiates cardiac electrical activity. Initial depolarizing electrical impulses are conducted rapidly to adjacent atrial cardiomyocytes by intracellular gap junctions, where they trigger the excitation and contraction of the atria that manifests as a P wave on surface ECG. Next, these excitatory impulses are propagated via the atrioventricular node and Purkinje
Penetrance, Expressivity, and Overlapping Phenotypes in Heritable Cardiac Arrhythmia Syndromes
In 1992, nearly 4 years before KCNQ1 (LQT1) was identified officially as the culprit gene residing within the chromosome 11p15.5 genetic locus that was closely linked with LQTS in several families, Vincent et al14 observed that there was a significant overlap between the heart rate-corrected QT intervals (QTc) in carriers (range 410 to 590 ms; mean 490 ms) and non-carriers (range 380 to 470 ms; mean 420 ms) of the 11p genetic marker. Coupled with the fact that 63% of 11p genetic marker carriers
Genetic Architecture of Electrocardiographic Traits
As mentioned previously, even in the general population quantitative electrocardiographic traits such as the QT interval are highly variable as evidenced by the observation that while nearly 40% of patients with genetically confirmed LQTS have non-diagnostic QT intervals, 5%–10% of ostensibly healthy individuals have a QTc exceeding the electrocardiographic guideline designation of “prolonged QTc” (≥450 ms in men and ≥460 ms in women) or “short QTc” (<350 ms for males and <360 ms for females,
Common Polymorphisms Modulating QT Interval in Health
The discovery that QT prolongation/shortening is associated with increased cardiovascular morbidity and mortality in apparently healthy individuals43, 44, 45 has sparked a concerted effort in recent years to elucidate the genetic determinants that modulate QT interval duration and SCD risk in the general population. Here, we briefly review the candidate and GWAS that have provided a great deal of insight into the heritable component of QT interval variation.
Most early studies focused on the
Genetic Determinants of Incomplete Penetrance and Variable Expressivity in Heritable Cardiac Arrhythmia Syndromes
At present, most studies looking to elucidate the genetic determinants of incomplete penetrance and variable expressivity in the cardiac channelopathies have focused on the co-inheritance of functional SNPs that influence the arrhythmia risk associated with a given disease-causative mutation by either enhancing or repressing the electrophysiological defect conveyed by that mutation. In most instances, these are amino acid-altering SNPs that reside on the opposite allele of the gene harboring
Emerging Role of Non-Coding Variants in the Allele-Specific Modification of Heritable Arrhythmia Syndrome Disease Severity
Despite a concerted effort over the past decade, it is clear that a significant proportion of the variability in disease penetrance and expressivity observed within many multigenerational cardiac channelopathy pedigrees cannot be explained by established environmental and genetic determinants alone. As such, it stands to reason that yet undiscovered elements within an individual’s genetic background underlie these genetic phenomena in the cardiac channelopathies. Here, we review several recent
Concluding Remarks
Advances at the bench and bedside have unearthed a number of important environmental and genetic determinants responsible for the marked variability in electrographic traits and risk of arrhythmia-associated symptoms observed in heath and disease. However, our enhanced understanding of the genetic determinants of incomplete penetrance and variable expressivity in the heritable cardiac arrhythmia syndromes has yet to translate into truly meaningful advances at the bedside. While we now
John Giudicessi, BA is an MD/PhD, candidate at the Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, MN. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2012.
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John Giudicessi, BA is an MD/PhD, candidate at the Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, MN. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2012.
This work was supported by the Windland Smith Rice Sudden Comprehensive Sudden Cardiac Death Program (to M.J.A.). J.R.G is supported by a NIH/NHLBI NRSA Ruth L. Kirschstein individual pre-doctoral MD/PhD fellowship (F30-HL106993).
MJA is a consultant for Transgenomic. Intellectual property derived from MJA’s research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals and now Transgenomic).