HCN4 – Familial Sick Sinus Syndrome

Familial sick sinus syndrome (SSS) is an autosomal dominant cardiac conduction disorder characterized by sinoatrial node dysfunction leading to bradycardia, sinus pauses and proneness to pacemaker dependence. Genetic screening of 38 unrelated families identified two heterozygous loss-of-function HCN4 variants, and meta-analysis of 48 SSS probands revealed 16 independent carriers of HCN4 mutations presenting with early‐onset disease (39.1 ± 21.7 y), frequent atrial fibrillation (43.8%) and left ventricular noncompaction (50%)^[PMID:28104484]. These data establish a distinct familial SSS subgroup linked to HCN4 haploinsufficiency.

Inheritance is autosomal dominant with segregation of HCN4 variants in at least two multiplex families showing concordant disease status^[PMID:28104484]. In total, 16 unrelated probands harbored rare heterozygous missense variants in HCN4, including c.1178G>A (p.Arg393His) and c.2648C>G (p.Pro883Arg), all absent from population databases and meeting pathogenicity criteria^[PMID:28104484]. The variant spectrum comprises primarily missense changes clustered in transmembrane or C-linker regions, consistent with critical channel domains.

Patch-clamp analysis of patient-derived HCN4 mutants demonstrated significant reduction in hyperpolarization‐activated current (If) for c.1178G>A (p.Arg393His) and c.2648C>G (p.Pro883Arg), confirming loss-of-function channel gating^[PMID:28104484]. The D553N variant exhibits dominant‐negative trafficking defects and If loss in heterologous systems^[PMID:15123648], while an embryonic zebrafish assay recapitulated bradycardia and phenotypic severity for multiple human HCN4 variants, distinguishing pathogenic from benign alleles^[PMID:28803248]. These concordant functional studies support haploinsufficiency as the primary disease mechanism.

HCN4 mutation carriers often require pacemaker implantation at an older age (43.5 ± 22.1 y) and display a higher prevalence of atrial fibrillation (43.8%) and left ventricular noncompaction (50%), distinguishing them from SCN5A‐related SSS^[PMID:28104484]. No studies to date have refuted the causal role of HCN4 LOF variants in familial SSS, although rare channel variants outside key functional domains may lack pathogenicity.

In summary, heterozygous loss-of-function HCN4 variants cause autosomal dominant familial SSS with early onset, frequent atrial fibrillation and left ventricular noncompaction. Functional assays uniformly demonstrate reduced If and trafficking defects, fulfilling ClinGen criteria for strong genetic and moderate experimental evidence. Genetic testing of HCN4 should be incorporated into diagnostic panels for SSS.

Key take-home: HCN4 haploinsufficiency underlies a clinically recognizable form of familial SSS with distinct arrhythmia and structural cardiac associations, supporting its inclusion in diagnostic and prognostic workflows.

References

• Heart Rhythm • 2017 • Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction. PMID:28104484
• The Journal of biological chemistry • 2004 • Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. PMID:15123648
• Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology • 2017 • A Functional Assay for Sick Sinus Syndrome Genetic Variants. PMID:28803248

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