The clinical and electrocardiographic phenotype of patients with genotype-negative long QT syndrome.

BACKGROUND

Long QT syndrome (LQTS) is a genetic heart disease that increases the risk of ventricular arrhythmias and sudden cardia arrest. Despite advances in genetic testing, a small subset of patients with LQTS remain genetically elusive.

OBJECTIVE

This study aimed to determine the prevalence and clinical characteristics of patients with a phenotype of LQTS but without a genotype.

METHODS

This study aimed to identify phenotype-positive, genotype-negative patients with LQTS seen at Mayo Clinic (2000-2024). Retrospective data included demographics, clinical evaluations, electrocardiograms, 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 1829 patients with LQTS. Of these, 1706 (93%) had pathogenic or likely pathogenic variants, and 95 patients (5%) had upgraded clinical 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, with 76% being women and an average initial corrected QT of 498 ± 41 ms. Fourteen patients (53%) experienced cardiac events prior to diagnosis, and 11 (44%) received an implantable cardioverter-defibrillator. 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.