Polymorphisms in the NOS1APGene Modulate QT Interval Duration and Risk of Arrhythmias in the Long QT Syndrome

Abstract

Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

“…Usually referred to as "variable penetrance of the disease," this observation has been attributed to largely undefined genetic modifiers (6,7). Studies of induced pluripotent stem cell-derived (iPS-derived) cells might shed light on the elusive role of genetic modifiers in arrhythmias (discussed in detail below).…”

Enhancing Literacy in Cardiovascular Genetics: A Scientific Statement From the American Heart Association

“…Aggregation of loci into genetic risk scores is being increasingly explored as a way to improve predictive ability for disease, as well as modifiers of disease phenotype, although this approach requires further validation. [108][109][110][111][112] Direct-to-consumer testing companies offer testing for variants associated with many common diseases, including cardiovascular diseases. The FDA issued a warning in 2013 prohibiting companies from providing direct health information to US consumers without FDA approval of the accuracy, reliability, and clinical utility of their tests.…”

Sudden Cardiac Death and Genetic Ion Channelopathies

“…30 -32 Although genotype-phenotype correlations are useful, interindividual variability exists and must be taken into account in the assessment of any given patient or family. Incomplete penetrance and variable expressivity are indeed common in LQTS 10 and may be explained by different causes: multiple mutations (compound or double heterozygosity), modulating coding single-nucleotide polymorphisms in the same gene (cis or trans) harboring the primary mutation, and different genetic combinations of subject-specific pools of single-nucleotide polymorphisms affecting the QT interval 33,34 ( Figure 2).…”

“…21 We believe that this observation questions the need for screening all patients on all the Risk stratification in long-QT syndrome (LQTS) including sex; QTc duration; LQT1, LQT2, and LQT3 genotype; and the NOS1AP genotype as a genetic modifier of the underlying main genetic defect. 34 …”