Compound heterozygous SCN5A mutations in severe sodium channelopathy with Brugada syndrome: a case report

Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in the SCN5A gene, encoding the main cardiac sodium Nav1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused by SCN5A compound heterozygous mutations. We performed genetic analysis of SCN5A in a male proband who collapsed during cycling at the age of two. Because of atrial standstill, he received a pacemaker and at the age of three he experienced a new collapse with left-sided brain stroke. A later ECG taken during fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Methods and results Next-generation sequencing allowed detection of two SCN5A variants in trans: c.4813+3_4813+6dupGGGT - a Belgian founder mutation - and c.4711 T>C, p.Phe1571Leu. Familial segregation analysis showed the presence of the founder mutation in the proband’s affected father and paternal aunt and de novo occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the β1-subunit. Compared to the SCN5A wild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide α-1 the variant’s loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. Conclusion This is the first report providing support for the pathogenicity of the p.Phe1571Leu SCN5A variant, which together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS phenotype in the presented case.