The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome

Background: Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Nav1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown.

Objective: The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases.

Methods: DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000-2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Nav1.5 channel complex: SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, SNTA1, and CAV3. Patch-clamp analyses were performed on variants not previously characterized.

Results: In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3, 1 rare variant (T78M); GPD1L, 1 rare variant (R220H); and SCN3B, 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A) predominantly revealed increased transient and sustained sodium current.

Conclusion: In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.