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

Abstract

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.

Keywords: HCN4; SCN5A; bradycardia; exome sequencing; genetic testing; in silico variant effect prediction; long QT syndrome.

Figure 1

Pedigree of the studied family (ages are given at the time of genetic testing). The proband is marked with the arrow. Colored figures represent the affected family members as follows: black color—the long QT phenotype; diagonal black–white shading—bradycardia without QT prolongation. The crossed-out figure corresponds to the deceased family member. Genetic variants found in the family are shown with colored dots.

Figure 2

Patients’ electrocardiograms (ages are given at the time of ECG examination). (A) Proband (21 years): atrial paced rhythm with native ventricular conduction, heart rate—60 bpm. First-degree AV block. QT = 500 ms, QTc = 500 ms; (B) Proband’s mother (47 years): atrial paced rhythm with native ventricular conduction, heart rate—50 bpm. Incomplete right bundle branch block. QT = 540 ms, QTc = 509 ms; (C) Proband’s brother II-1 (27 years): sinus rhythm with a heart rate of 61 bpm. QT = 378 ms, QTc = 381 ms; (D) Proband’s brother II-2 (26 years): sinus bradyarrhythmia with a heart rate of 51–57 bpm. Right bundle branch block. QT = 500 ms, QTc = 483 ms; (E) Proband’s brother II-5 (19 years): atrial paced rhythm with native ventricular conduction, heart rate—50 bpm. QT = 560 ms, QTc = 529 ms; (F) Proband’s sister (18 years): sinus bradycardia with a heart rate of 51 bpm. Sinus arrhythmia. QT = 400 ms, QTc = 373 ms.