The Role of Genetic Mutations, Sodium Channel Dysfunction, and Cardiac Arrhythmia in the Pathogenesis of SIDS
Introduction. Sudden Infant Death Syndrome, or SIDS, describes the condition in which a baby unexplainedly dies during its first year of life.1,3 SIDS is the leading cause of death in post-neonates (28 days to 1 year), and the third leading cause of infant deaths.1,3 In 1998, SIDS was directly linked to cardiac arrhythmias caused by mutated ion channels that dysregulate electric excitation of the heart. 2,3 10-15% of SIDS cases have been linked to a genetic cause, half of which have been attributed to the SCN5A gene.2,5 A strong correlation has also been discovered between the protein Connexin43 and SIDS.3 Recently, epileptic genes such as SCN1A have being investigated as a potential contributor to cardiac arrhythmia too.1 Because of the incomplete penetrance of the inherited genetic mutants discussed, there is likely other genetic, epigenetic, and environmental contributors to the inheritance of the SIDS phenotype.1,2 Methods. Statistical analysis of each study and experiment utilizes the p-value, which measures the statistical significance of a data set taking into account the study’s sample size (n). The p-value, expressed as a percentage, reflects the chance that the experimental results obtained are a statistical outlier. Therefore, if the calculated p-value is less than 0.05 or 5%, the null hypothesis is rejected and the data set is considered statistically significant. Polymorphism Phenotyping v2 was used to assess the probability that specific gene variations are disease-causing.5 Results. Genetic analysis revealed the SCN5A, CX43E42K, and SCN1A genes linked to SIDS. Using NEK cells, mutations in these genes were compared to wild type. Results confirmed the hypothesis that mutations in these genes are correlated to cardiac arrhythmia by dysregulating sodium channels. Sodium channels are important of phase of cardiac depolarizations, so mutations directly contribute to arrhythmia. Conclusions. SIDS has been shown to have a causative link with cardiac dysfunction. While the exact pathogenic mechanism of SIDS is still highly debated and researched, genetic mutations that result in defective ionic channel proteins have contributed to a substantial amount of deaths by SIDS. Connexin43 and SCN1A should be further investigated in the future of molecular research about SIDS, as they are recently new discoveries in the field.3,4
- Brownstein CA, Goldstein RD, Thomspon CH, et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia. 2018; 59(4):56-62.
- Denti F, Bentzen BH, Wojciak J, et al. Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome. Pacing Clin Electrophysiol. 2018;42(6):620-626.
- Lubkemeier I, Bosen F, Jung-Sun K, et al. Human Connexin43E42K mutation from a sudden infant death victim leads to impaired ventricular activation and neonatal death in mice. Circ Cardiovasc Genet. 2015;8(1):21-9
- Mishra S, Reznikov V, Maltsev VA, et al. Contribution of sodium channel neuronal isoform Nav1.1 to late sodium current in ventricular myocytes from failing hearts.
- Stroh van Deventer B, du Toit-Prinsloo L, van Niekerk C. Feasibility of analysis of SCN5A gene in paraffin embedded samples in sudden infant death cases at the Pretoria Medico-Legal Laboratory, South Africa. Forensic Sci Med Pathol. 2018;14: 276-284