A Novel Bradycardia-Associated Variant in HCN4 as a Candidate Modifier in Type 3 Long QT Syndrome: Case Report and Deep In Silico Analysis

<b>Background:</b> 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. <b>Case presentation:</b> We describe a three-generational family affected with clinically heterogeneous LQTS type 3 and bradycardia in which a novel missense variant p.V642M in <i>HCN4</i> was identified in addition to the known pathogenic variant p.E1784K in <i>SCN5A</i>. 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 <i>HCN4</i> variant in sinus bradycardia and its possible contribution to the phenotypic heterogeneity of LQTS type 3. <b>Conclusions:</b> This case is the first description of a functional variant in <i>HCN4</i> as a candidate modifier in LQTS type 3 and demonstrates the importance of analyzing additional genetic variations in families with complex LQTS phenotypes.