Abstract 2455: Genetic Factors Conferring Congenital Sick Sinus Syndrome in SCN5A Mutation Carriers
Sick sinus syndrome (SSS) is frequently associated with aging or underlying heart diseases, but it may occur in a congenital form with variable mode of inheritance. Congenital SSS often appears to be sporadic, conditions that have hampered identification of the responsible genes and its pathophysiology. To elucidate genetic basis underlying congenital SSS, we focused on two families with an apparently sporadic case of SSS, and genetically screened Na channel α subunit (SCN5A) and atria-specific genes including connexin 40 (Cx40). The proband of an SSS family K1, who underwent pacemaker implantation at age 5 years, exhibited compound heterozygosity for two distinct SCN5A mutations: a missense mutation M1880V inherited from his mother, and an in-frame deletion/insertion mutation resulting in substitution of Ser for Met-Ser-Asn at codons 801–803 (801–803S) inherited from his father. Family members carrying only one of these alleles showed normal ECG. Consistent with the clinical observations, heterologously expressed mutant channels of M1880V or 801–803S showed relatively benign biophysical abnormalities, suggesting that single SCN5A mutation may not be sufficient to cause severe sinus node dysfunction. Moreover, in the proband (age 18 years) of the kindred K2, we found a novel SCN5A mutation R219H. Heterologously expressed R219H channel was non-functional, probably because the mutation is located at the putative activation gate of the Na channel. Interestingly, her mother showed normal ECG despite carrying the non-functional R219H allele. Further genetic screening revealed that the proband, but not other K2 family members, carried homozygous single nucleotide polymorphisms (SNPs) in the regulatory region of Cx40 (−44AA, +71GG) which reduce Cx40 expression level in vitro, thereby disrupt normal atrial electrical coupling and excitation. Our study suggests that congenital SSS is a cardiac Na channelopathy, but a single mutant allele may not be sufficient to confer a severe clinical phenotype. Coinheritance of an additional SCN5A mutation on the other allele (recessive inheritance) or Cx40 SNPs (digenic inheritance) may have a significant impact on sinus node function, and explain in part the variable mode of transmission.