Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

Abstract

Background Brugada syndrome (Brs) and long QT syndrome (LQTs) are the most observed “inherited primary arrhythmia syndromes” and “channelopathies”, which lead to sudden cardiac death. Methods Detailed clinical information of Brs and LQTs patients was collected. Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing on the Illumina HiSeq 2000 platform. Then, we performed bioinformatics analysis for 200 genes susceptible to arrhythmias and cardiomyopathies. Protein interaction and transcriptomic co-expression were analyzed using the online website and GTEx database. Results All sixteen cases of Brs and six cases of LQTs were enrolled in the current study. Four Brs carried known pathogenic or likely pathogenic of single-point mutations, including SCN5A p.R661W, SCN5A p.R965C, and KCNH2 p.R692Q. One Brs carried the heterozygous compound mutations of DSG2 p.F531C and SCN5A p.A1374S. Two Brs carried the novel heterozygous truncated mutations (MAF < 0.001) of NEBL (p.R882X) and NPPA (p.R107X), respectively. Except for the indirect interaction between NEBL and SCN5A, NPPA directly interacts with SCN5A. These gene expressions had a specific and significant positive correlation in myocardial tissue, with high degrees of co-expression and synergy. Two Brs carried MYH7 p.E1902Q and MYH6 p.R1820Q, which were predicted as "damaging/possibly damaging" and "damaging/damaging" by Polyphen and SIFT algorithm. Two LQTs elicited the pathogenic single splicing mutation of KCNQ1 (c.922-1G > C). Three LQTs carried a single pathogenic mutation of SCN5A p.R1880H, KCNH2 p.D161N, and KCNQ1 p.R243S, respectively. One patient of LQTs carried a frameshift mutation of KCNH2 p. A188Gfs*143. Conclusions The truncated mutations of NEBL (p.R882X) and NPPA (p.R107X) may induce Brugada syndrome by abnormally affecting cardiac sodium channel. SCN5A (p.R661W, p.R965C and p.A1374S) and KCNH2 (p.R692Q) may cause Brugada syndrome, while SCN5A (p.R1880H), KCNQ1 (c.922-1G > C and p.R243S) and KCNH2 (p.D161N and p.A188Gfs*143) may lead to long QT syndrome.

Brugada Syndrome: More than a Monogenic Channelopathy

“…In particular, a decrease in current density, a positive shift in the activation curve, a negative shift in the inactivation curve, or a loss of regulation by intracellular factors such as PKA, ankyrin G or a1-syntrophin have been described [22,29,[37][38][39][40][41] (Figure 2). Consistently, cardiomyocytes derived from mice models or patients' stem cells displayed a reduction in INa density and a reduction in AP upstroke velocity and altered ECG parameters [42].…”

“…The variants can either impair membrane trafficking or modify channel gating properties or kinetics or cause haploinsufficiency determined by premature transcriptional stop signals. In particular, a decrease in current density, a positive shift in the activation curve, a negative shift in the inactivation curve, or a loss of regulation by intracellular factors such as PKA, ankyrin G or a1-syntrophin have been described [ 22 , 29 , 37 , 38 , 39 , 40 , 41 ] ( Figure 2 ).…”

“…Sporadic gain-of-function variants in genes coding for Kv4.3 accessory subunits ( KCNE3, KCNE5, KCNAB2 ) increase Ito indirectly and also lead to BrS [ 73 , 74 , 75 ]. By a similar mechanism, variants that induce an increase in other repolarizing currents (IK-ATP and IKr) may predispose to BrS [ 41 , 67 ].…”

Brugada syndrome: from genetics, diagnosis to clinical therapy

“…The aforementioned variants may impair membrane trafficking, modify channel gating properties or kinetics, or cause haploinsufficiency due to premature transcriptional stop signals. Specifically, previous research has revealed a decrease in I Na and I K1 density and conduction www.cardiologyplus.org Huang K and Ren J: Cardiology Plus velocities or a loss of regulation by intracellular factors in signal transduction, including protein kinase A (PKA), ankyrin G, or a1-syntrophin [20][21] .…”