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

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