Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

TLDR

Sick sinus syndrome is an arrhythmia caused by sinus node dysfunction, diagnosed by bradycardia or arrest, and while common in the elderly, it can also occur in children without obvious heart disease, suggesting a congenital form. The study aimed to identify SCN5A mutations as a candidate cause of congenital SSS by screening ten pediatric patients from seven families. Researchers screened the SCN5A α‑subunit in these patients and performed functional assays on identified variants expressed in recombinant human heart sodium channels. Probands from three families carried compound heterozygous SCN5A mutations, including two previously dominant variants, and functional studies showed loss‑of‑function or gating defects that predict reduced myocardial excitability, establishing a recessive molecular basis for congenital SSS.

Abstract

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.