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A rare HCN4 variant with combined sinus bradycardia, left atrial dilatation, and hypertrabeculation/left ventricular

Marta Alonso-Fernández-Gatta1, María Gallego-Delgado2, Ricardo Caballero3

  • 1Servicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.

Revista Espanola De Cardiologia (English Ed.)
|October 3, 2020
PubMed

Insights

A novel HCN4 gene variant (p.R375C) is linked to a familial heart disorder combining sick sinus syndrome (SSS), left atrial dilatation (LAD), and left ventricular noncompaction (LVNC) cardiomyopathy. This genetic finding aids in diagnosing these interconnected cardiac conditions.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Electrophysiology

Background:

  • Sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy are distinct cardiac conditions.
  • HCN4 gene variants are known causes of SSS, but their association with LVNC and left atrial dilatation (LAD) is less understood.
  • Familial clustering of these conditions suggests a potential shared genetic etiology.

Purpose of the Study:

  • To investigate a family exhibiting a combined phenotype of SSS, LAD, and LVNC/hypertrabeculation.
  • To identify the genetic variant responsible for this familial cardiac disorder.
  • To characterize the electrophysiological consequences of the identified genetic variant.

Main Methods:

  • Clinical assessment including ECG, Holter monitoring, echocardiography, and cardiac MRI.
  • Targeted next-generation sequencing for genetic analysis.
  • Functional studies of the candidate HCN4 variant in vitro (CHO cells).

Main Results:

  • A novel heterozygous HCN4 variant, c.1123C>T (p.R375C), was identified in all affected family members.
  • Affected individuals presented with sinus bradycardia, LAD, and varying degrees of LVNC or hypertrabeculation.
  • Functional studies revealed significantly reduced HCN4 channel currents (IHCN4) with the p.R375C mutation.

Conclusions:

  • The familial co-occurrence of SSS, LAD, and LVNC is associated with the heritable HCN4 p.R375C variant.
  • This finding expands the known spectrum of HCN4-related cardiac disorders.
  • HCN4 variants should be considered in the genetic diagnostics of familial SSS, LVNC cardiomyopathy, and sinus bradycardia with LAD.
Abstract

Keywords:
Bradicardia sinusalDilatación de la aurícula izquierdaHCN4HipertrabeculaciónHypertrabeculationLeft atrial dilatationMiocardiopatía no compactadaNoncompaction cardiomyopathySinus bradycardia

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