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

Rev Esp Cardiol (Engl Ed). 2021 Sep;74(9):781-789. doi: 10.1016/j.rec.2020.06.019. Epub 2020 Sep 30.
[Article in English, Spanish]

Abstract

Introduction and objectives: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics.

Methods: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells.

Results: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (IHCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels.

Conclusions: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.

Keywords: Bradicardia sinusal; Dilatación de la aurícula izquierda; HCN4; Hipertrabeculación; Hypertrabeculation; Left atrial dilatation; Miocardiopatía no compactada; Noncompaction cardiomyopathy; Sinus bradycardia.

MeSH terms

  • Animals
  • Bradycardia / diagnosis
  • Bradycardia / genetics
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dilatation
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels* / genetics
  • Muscle Proteins / genetics
  • Phenotype
  • Potassium Channels / genetics
  • Sick Sinus Syndrome* / diagnosis
  • Sick Sinus Syndrome* / genetics

Substances

  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Muscle Proteins
  • Potassium Channels