Association of common and rare variants of SCN10A gene with sudden unexplained nocturnal death syndrome in Chinese Han population

Abstract

Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unknown etiology to both forensic pathologists and physicians. The electrocardiogram (ECG) characteristics and clinical phenotype of SUNDS survivors strongly suggest that SUNDS shares some similarities with Brugada syndrome (BrS). Recently, the variants of sodium channel Na 1.8 coding gene SCN10A were identified to be associated with BrS. Here, we investigated the association of SCN10A gene variants with 105 sporadic SUNDS victims and 22 BrS cases in the Chinese Han population. A total of 6 rare mutations and 16 polymorphisms were detected in SUNDS victims. Of the six rare mutations, two were putative pathogenic mutations (F386C and R1263*), one was a likely pathogenic mutation (R14H), and the other three were predicted as benign (R817Q, T1181M, and P1683S). As for the 16 polymorphisms, 1 was a novel polymorphism (c.4144-84G>A) located in intron 24, and the rest were reported previously including one polymorphism (c.2884A>G [I962V]) which showed a statistically significant difference in allele frequency (p = 0.044) between SUNDS and the control group. There were also 5 rare mutations and 15 polymorphisms detected in BrS cases. This is the first report of common and rare variants of SCN10A gene in SUNDS and BrS in the Chinese Han population, which provides the genetic epidemiological evidence that SCN10A may be a novel susceptibility gene for SUNDS and account for approximately 3 % of SUNDS in China.

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population

“…SUNDS, a clinical conundrum in both forensic and clinical medicine, has a strong genetic underpinning based on reported molecular pathological studies . Accumulated evidence suggests that SUNDS is related primarily to cardiac arrhythmia diseases, such as BrS, long QT syndrome, sick sinus syndrome, and cardiac conduction disease .…”

“…Genomic DNA was extracted from blood samples as reported previously . All coding regions and exon‐intron boundaries for XIRP1 and XIRP2 (GenBank and , respectively) were polymerase chain reaction amplified using designed primers (Table ).…”

“…It has been implicated that genes within highly conserved syntenies may be functionally related . The XIRP1 ‐containing locus also harbors the SCN5A and SCN10A genes that encode cardiac sodium channels and are known to be associated with BrS, long QT syndrome, and SUNDS . On the other hand, XIRP2 ‐containing locus has not been linked to cardiac arrhythmia, but deletion of chromosome band 2q24 has been associated with congenital heart defects …”

Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma

“…Two rare missense variants (R14H and F386C) were predicted as likely pathogenic, while the remaining 3 (R817Q, T1181M, and P1683S) were benign. As for the 16 common SNPs, only c.2884A>G (I962V) had a statistically significant difference in allele frequency, with an odds ratio of 1.551for G allele, between SUNDS and the controls …”

Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population

“…Similarly, our molecular autopsy of the BrS-associated genes ( SCN5A , SCN1B-4B , SCN10A , MOG1 , and GPD1-L ) could only account for a small part of the genetic cause of SUNDS victims [6, 7], indicating that a majority of SUNDS may be due to other genetic bases.…”