Heart Rhythm. 2025 May 29:S1547-5271(25)02513-5. doi: 10.1016/j.hrthm.2025.05.053. Online ahead of print.
ABSTRACT
BACKGROUND: Long QT syndrome (LQTS) is a genetic heart disease that increases the risk for ventricular arrhythmias and sudden cardia arrest. Despite advances in genetic testing, a small subset of LQTS patients remain genetically elusive.
OBJECTIVE: To determine the prevalence and clinical characteristics of patients with a phenotype of LQTS but genotype negative.
METHODS: This study aimed to identify phenotype-positive, genotype-negative LQTS patients seen at Mayo Clinic (2000 - 2024). Retrospective data included demographics, clinical evaluations, ECGs, and genetic results. Diagnosis adhered to established criteria, and genotype-negative LQTS was defined by the absence of pathogenic variants despite clinical presentation.
RESULTS: The study included 1,829 patients with LQTS. From these, 1,706 (93%) had pathogenic or likely pathogenic variants and 95 patients (5%) had upgraded clinically variants of uncertain significance, leaving 32 (1.7%) with negative genetic tests. Among the genotype-negative patients, 17 underwent next-generation sequencing, identifying a genetic cause in 6 cases (0.3% of the total). The mean age at diagnosis for the remaining 26 patients was 25 ± 15 years, 76% being female and an average initial QTc of 498 ± 41 ms. Fourteen patients (53%) experienced cardiac events prior to diagnosis, and 11 (44%) received an implantable cardioverter-defibrillator (ICD). The mean follow-up period was 8 ± 7 years.
CONCLUSION: Genotype-negative LQTS accounted for <2% of our cohort, highlighting diagnostic and management challenges. Comprehensive clinical evaluation and advanced genetic testing remain essential for accurate diagnosis and care.
PMID:40449819 | DOI:10.1016/j.hrthm.2025.05.053