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

Orphanet J Rare Dis. 2022 Oct 27;17(1):394. doi: 10.1186/s13023-022-02542-z.


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.

Keywords: Arrhythmia; Brugada syndrome; Long QT syndrome; Natriuretic peptide precursor A; Nebulette.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brugada Syndrome* / genetics
  • ERG1 Potassium Channel / genetics
  • Exome Sequencing
  • Humans
  • KCNQ1 Potassium Channel / genetics
  • Long QT Syndrome* / genetics
  • Mutation / genetics
  • NAV1.5 Voltage-Gated Sodium Channel / genetics


  • KCNQ1 Potassium Channel
  • ERG1 Potassium Channel
  • NAV1.5 Voltage-Gated Sodium Channel
  • N-propionylprocainamide