Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report

Abstract

Aims: 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 Na v 1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused by SCN5A compound heterozygous mutations. We performed a genetic analysis of SCN5A in a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a 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 the detection of two SCN5A variants in trans: c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and the de novo occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the β 1-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. Nijak et al. Functional Characterization of p.Phe1571Leu in SCN5A 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 in the presented case.

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

“…Compound heterozygosity is infrequent in SCN5A channelopathies, reported only in 13/2111 (0.62%) of BrS patients [ 31 ], and in 0.7% of neonates with SCN5A mutations [ 15 ]. Moreover, among ten individual SCN5A compound heterozygous case reports [ 12 , 13 , 27 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], only two cases reported adult age of onset [ 35 , 36 ], and 6/8 childhood onset cases had a truncating mutation combined with a missense mutation [ 12 , 27 , 32 , 33 , 34 ]. All three of our compound heterozygous cases (cases 8, 10 and 13) carried an inferred null and a missense mutation, had a severe overlap syndrome with early childhood onset (<4 years), and NFCA events occurred in two of these cases.…”

“…Early age of onset is associated with severity in many genetic diseases. Although there are many isolated case-reports of SCN5A -channelopathy in children in the medical literature [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], few studies have analyzed SCN5A -channelopathy cohorts where onset of symptoms occurs in pediatric patients. A large prospective multi-center pediatric cohort of SCN5A mutation-positive neonates reported that 67.9% were asymptomatic at diagnosis, while age <1 year at diagnosis, compound heterozygous mutations, and mutations with both gain- and loss-of-function were identified as independent risk factors for cardiac events [ 15 ].…”

Functional Characterization of the Nemertide α Family of Peptide Toxins

“…However, the notorious Nav1.5 may now emerge as a potential drug target. Recently, Nijak et al showed that nemertide 1 was able to restore the loss of function by reducing channel inactivation by binding to Na V 1.5 in a rare inherited cardiac arrhythmia . Nemertide 4 , which normally would be immediately disqualified as the most toxic peptide because it is the most active on Na V 1.5, might thus be the most interesting one.…”