Clinical characterization of the first Belgian SCN5A founder mutation cohort

Abstract

Aims We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. Methods and results The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. Conclusion The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review

“…A majority of rare SCN5A variant carriers do not have BrS [ 7 , 60 ], while most BrS patients do not have SCN5A mutations [ 2 ]. Additionally, carriers of a specific SCN5A mutation may have different clinical phenotypes, as shown by the aggregation of various cardiac disorders within the same family and in cohorts with the same mutation [ 30 , 61 ]. Various members of a family may present with syncope, atrial fibrillation, sick sinus syndrome, or may be asymptomatic [ 30 ].…”

Morpho-functional comparison of differentiation protocols to create iPSC-derived cardiomyocytes

“…Commercial fibroblasts – BJ (ATCC ® CRL-2522™) (referred to as Control 1) were thawed and cultured for 8 days prior to reprogramming. Skin biopsies from one healthy control donor (Control 2) and two BrS patients (BrS patient 1 and 2 –carrying the same SCN5A variant: a Belgian BrS founder mutation c.4813+3_4813+6dupGGGT; Sieliwonczyk et al, 2021 ) were obtained using standard procedures and processed on the day of collection as follows: after mechanical cutting, sample underwent enzymatic digestion in 37°C in a mixture of trypsin (Life Technologies) and collagenase type IV (Sigma-Aldrich) (1:1) for 1 h. Cells were brought to culture in a T25 flask (Corning) in fibroblast culture media consisting of RPMI1640 media (Life Technologies) supplemented with 10% FBS (Life Technologies), 1% of Penicillin/Streptomycin (Life Technologies), 1% of sodium pyruvate (Sigma-Aldrich) and 0.1% of primocin (InvivoGen Europe), and cultured in 5% CO 2 humidified conditions in 37°C up to 3 weeks.…”

Generation of two induced pluripotent stem cell (iPSC) lines (BBANTWi006-A, BBANTWi007-A) from Brugada syndrome patients carrying an SCN5A mutation

“…This mutation has been reported twice but was not yet studied in cardiomyocytes ( Hong et al, 2005 , Rossenbacker et al, 2005 ). The clinical spectrum of mutation carriers ranges from asymptomatic over abrupt syncopes to a significant number of SCD ( Sieliwonczyk et al, 2021 ). To study the mechanism of this phenotypical variability, two iPSC lines from SCN5A founder mutation carrier siblings are generated ( Table 1 ), one from a symptomatic patient (BBANTWi006-A) and one from an asymptomatic (BBANTWi007-A) mutation carrier and will be differentiated into iPSC-derived cardiomyocytes.…”