Key result
A polygenic combination of a variant of unknown significance (hERG-A913V) and a more severe mutation (hERG-S654G) produced additive effects leading to a prolonged QTc in the proband.
Case Report (n=5)
No
Functional characterization and computational modeling revealed that a combination of multiple genetic variants, including a variant of unknown significance, can additively cause a polygenic long QT syndrome phenotype.
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Highlights diagnostic pitfalls from VUS in LQTS genetic testing; leaves open need for refined classification before broader screening adoption.
Long QT syndrome (LQTS) is a disorder of cardiac repolarization characterized by a prolonged QT interval on electrocardiogram (ECG). LQTS usually is referred to as a monogenic disorder.1 QT interval in the population is variable,2 which leads to many “borderline” cases and makes definitive diagnosis difficult.1 The utility of clinical genetic screening in congenital LQTS has been demonstrated,3 although issues remain with variants of unknown significance (VUS), false positives, and false negatives.
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Hoshi et al. (2015) conducted a case report in Long QT syndrome (n=5). Polygenic mutations (SCN5A-F1596I, hERG-S654G, hERG-A913V) vs. Wild type / unaffected status was evaluated on Action potential duration (APD) prolongation and QTc. A polygenic combination of a variant of unknown significance (hERG-A913V) and a more severe mutation (hERG-S654G) produced additive effects leading to a prolonged QTc in the proband.
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