Abstract Body (Do not enter title and authors here): Background: LQTS is a genetic heart disease associated with an increased risk of sudden death. Despite advances in genetic testing, a small subset of patients still lacks identifiable genetic markers. Consequently, the true prevalence and clinical phenotype of genotype negative remains to be determined.
Objective: To determine the prevalence and clinical characteristics of patients with a clinical diagnosis of LQTS but a negative genetic test.
Methods: A retrospective review was conducted on patients evaluated and treated at a tertiary hospital between 2000 and 2024, focusing on those with a clinical diagnosis of LQTS, but a negative genetic test for all LQTS-associated genes, with available follow-up of at least 1 year.
Results: After exclusion for follow-up and lack of genetic testing, the study cohort consisted of 1834 patients with LQTS including 1708 (93%) with a (likely) pathogenic (LP/P), LQTS-causative variant. Also, in 95 patients (5%), their variant of uncertain significance was clinically upgraded to a LP/P-variant, leaving only 31 patients classified as phenotype positive but genotype negative (1.6%). Of these, 16/31 underwent next-generation genetic sequencing, revealing the genetic cause in 6/16 cases (37%; 0.3% of all patients). For the remaining 25 genotype negative LQTS patients (1.3%), the mean age at diagnosis was 26 ± 15 years, with 19 (76%) being female, and an average initial QTc of 497 ± 41 ms. In total, 11 patients (44%) experienced a cardiac event before diagnosis [1 sudden cardiac arrest (SCA), 1 Torsades, 1 VT, 8 syncopes] and 1 patient had his first cardiac event during follow-up; 7/12 patients had more than one subsequent event. Twenty patients were proband (80%) and 6 had a family history of SCA. Eleven patients received an ICD (44%), left cardiac sympathetic denervation was performed in 4 (16%), and 2 patients experienced arrhythmia-related deaths (8%). The mean follow-up since diagnosis was 7 ± 5 years.
Conclusion: With a prevalence of genotype-negative LQTS of 2%, the number of these patients is much lower than previously suggested, underscoring the advancements in identifying new genetic markers and the role of phenotype-enhanced variant adjudication and next-generation sequencing. Additionally, significant disease severity was observed in the remaining patients, emphasizing the pivotal role of genotype-phenotype correlations and risk stratification in managing and counseling patients lacking identified LQTS-causing mutations.