Clinical Features, Long-Term Prognosis, and Clinical Management of Genotype-Negative Long QT Syndrome Patients

Background: Approximately 15% to 20% of patients clinically diagnosed with long QT syndrome (LQTS) are genotype-negative (GEN−). Whether they have a different arrhythmic risk or should be managed differently remains unclear, often leading to incomplete treatment. Objectives: The purpose of this study was to compare clinical aspects of GEN− and genotype-positive (GEN+) LQTS patients. Methods: We retrospectively evaluated 832 LQTS patients genetically screened in Japan (n = 347) and Italy (n = 485), including 698 with a disease-causing variant in the KCNQ1, KCNH2, and SCN5A genes (GEN+), and 134 without variants in these LQTS-related genes (GEN−). Results: At diagnosis, the Japanese patients were more often probands (86% vs 60%), symptomatic (39% vs 18%), and of younger age than the Italian patients; conversely, they used less β-blockers (65% vs 95%), more rarely had a family history (FH) of LQTS (42% vs 73%), and had more cardiac events during follow-up (13% vs 4%) (P < 0.001 for all comparisons). Within the Japanese cohort, the GEN− had more cardiac arrests, used less β-blockers, and had much less FH for LQTS compared their GEN+ counterpart. The Italian cohort was more homogeneous, with just more LQTS FH among the GEN+. QTc shortening (close to 30 ms in all groups) during follow-up was similar between Japanese and Italian patients, irrespective of their being GEN+ or GEN−. In both cohorts, during an average follow-up of 6 and 7 years, respectively, GEN+ and GEN− patients showed a comparable clinical outcome. Conclusions: Arrhythmic risk is similar between GEN+ and GEN− LQTS patients; they should be managed and treated in the same way.