Why the study?
In severe and complex long QT syndrome cases, a single disease-causing variant may not explain all clinical features, making the search for genetic modifiers beneficial for precise diagnosis and management.
This case report identifies a novel functional variant in HCN4 as a candidate modifier in LQTS type 3, highlighting the importance of analyzing additional genetic variations in families with complex LQTS phenotypes.
Novel HCN4 variant may modify LQTS3 phenotype; leaves open its role as modifier pending validation in larger cohorts.
Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial for precise diagnosis and management. Case presentation: We describe a three-generational family affected with clinically heterogeneous LQTS type 3 and bradycardia in which a novel missense variant p.V642M in HCN4 was identified in addition to the known pathogenic variant p.E1784K in SCN5A. We performed the detailed clinical investigation of the family and a deep in silico analysis of the discovered variants, showing the causal role of a new HCN4 variant in sinus bradycardia and its possible contribution to the phenotypic heterogeneity of LQTS type 3. Conclusions: This case is the first description of a functional variant in HCN4 as a candidate modifier in LQTS type 3 and demonstrates the importance of analyzing additional genetic variations in families with complex LQTS phenotypes.
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Букаева et al. (2025) studied this question.
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