Investigating the Diagnostic Yield of Analyzing larger Gene Pannels in Patients suspicious of Long-QT-Syndrome

Introduction: To date, there are at least 17 genes known to be associated with Long QT Syndrome (LQTS). Previously, genetic testing included 5 genes (KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A) which are known to account for > 75% of genotype positive patients. Especially due to technical advancements, it is now possible to include a larger gene panel in current testing strategies. However, it remains unclear whether the diagnostic yield can be improved by analyzing larger gene panels.

 

Objective: To evaluate whether more patients are diagnosed with LQTS when a larger gene panel is analyzed.

 

Methods: Retrospectively, we analyzed all index patients suspicious of LQTS, e.g. by Schwartz-Score, that had been genetically tested from 2013-2024. Family members receiving target testing only were excluded. In group 1 only five genes (KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A) and in group 2 more than those five genes had been examined. We evaluated both the number of genetic variants as well as the variant classification observed in both groups.  Groups were compared using Fisher’s exact test.

 

Results: From 2013 to 2024 a total number of 183 index patients were genetically tested. In 86 patients, the 5 gene panel (group 1) and in 97 patients a panel including more than these 5 genes (group 2) was analyzed. Genetic variants were found in 39/86 (45,3%) patients in group 1 and in 50/97 (51,5%) patients in group 2 (Fig.1A, p=0.46). Among those genetic variants, 25/39 (64,1%) were classified as pathogenic (P) or likely pathogenic (LP) in group 1, whereas in group 2 30/50 (60,0%) variants were classified as P/LP (Fig.1B, p=0.87). In 3 patients (10%) of genotype-positive patients in group 2 P/LP variants were found in KCNJ2 that would have not been detected using a 5-gene panel (Fig.1C, p=0.24).

 

Conclusion: Analyzing larger gene panels allows diagnosis of LQTS in an additional 10% of patients. Follow-up studies are needed to evaluate whether these families clinically benefit from LQTS diagnosis in index patients allowing optimized risk assessment and prevention both in index patients and family members.

 


Figure 1. Genetic testing in patients suspicious of LQTS. In group 1 only 5 major genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) and in group 2 more than these 5 genes were analyzed. A, Percentage of patients with any genetic variant. B, Percentage of patients with only pathogenic or likely pathogenic (P/LP) genetic variants. C, Percentage of patients from group 2 with P/LP variant in 5 major genes and in additionally tested genes. Fisher‘s exact test.