The sodium channel gene SCN5A and potassium channel genes KCNQ1 and KCNH2 have been widely reported to be genetic risk factors for arrhythmia including Brugada syndrome and long QT syndrome (LQTS).
Brugada syndrome has a similar prevalence in families with SCD and PAS as in families with SCD alone, although SCD in families with SCD and PAS occurs in more family members and at older age, while SCN5A mutations in these families are rare.
Our genetic screening of SCN5A in 65 consecutive BrS probands revealed two patients with overlapping phenotypes: one carried an SCN5A R1632C (in domain IV-segment 4), which we have previously reported, the other carried a novel SCN5A N1541D (in domain IV-segment 1).
We here screened the coding sequence, the flanking intronic regions as well as the 5' and 3'UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS.
We here engineered human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the CRISPR/Cas9 introduced BrS-mutation p.A735V-Na<sub>V</sub>1.5 (g.2204C > T in exon 14 of SCN5A) as a novel model independent of patient´s genetic background.
Mutations within SCN5A are found in a significant proportion (15-30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions.
Long QT type 1 (gene, KCNQ1) and CPVT (gene, RyR2) typically present with cardiac events (ie syncope or cardiac arrest) during or immediately after exercise in young males; long QT type 2 (gene, KCNH2) after startle or during the night in adult females-particularly early post-partum, and long QT type 3 and Brugada syndrome (gene, SCN5A) during the night in young adult males.
Furthermore, a genome-wide association study revealed that a common variant in SCN10A or HEY2 in addition to SCN5A is associated with BrS, thus, BrS may not be a monogenic Mendelian disease but probably an oligogenic disease.
Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient.
As proof-of-concept we extracted the wild-type and mutant of exon 12 and exon 17 of SCN5A genetic DNA from patients with long QT syndrome or Brugada syndrome by touchdown PCR and performed a successful point mutation discrimination in the AMDM platform.
Brugada syndrome (BrS) is an inherited cardiac arrhythmia commonly associated with SCN5A mutations, yet its ionic mechanisms remain unclear due to a lack of cellular models.
Dermal fibroblasts from a Brugada syndrome patient with a mutation in SCN5A (c.1100G>A, leading to Na<sub>v</sub>1.5_p.R367H) were reprogrammed to iPS cells.