Long QT syndrome (LQTS) is the most comprehensively researched inherited arrhythmia disorder, with more than 20 years of experience in investigational and clinical use of genetic testing, resulting in about 80% to 85% of currently tested patients identified with pathogenic gene variants.1-4 The LQT1 and LQT2 genotypes caused by potassium ion channels dysfunction account for about 80% to 85% of the reported LQTS cases, whereas LQT3, caused by impaired closing of the cardiac sodium channel, accounts for about 5% to 13% of genotyped patients with LQTS.1-4 In 1998, we documented for the first time, to our knowledge, a significant association between LQTS genotype and risk of cardiac events2 further enriched in the risk stratification by Priori et al.3 There is a substantial variation within LQTS subtypes and even within families segregating the same variants in penetrance and expression of disease. Modifying factors are of interest to better understand the disease process, improve risk stratification, and optimize therapy. In 2003, we reported strong modifying effects of age and sex on the clinical course of LQTS by genotype, demonstrating a significant age-sex-genotype interaction.4 Subsequently, international collaboration led by Moss et al and Barsheshet et al,5,6 Shimizu et al,7 and Wilde et al8 contributed to further characterization of LQT1, LQT2, and LQT3 phenotype-genotype correlations, although study populations consisted predominantly of white individuals.