Genotype and clinical characteristics of congenital long QT syndrome in Thailand.

Congenital long QT syndrome (LQTS) is an inheritable arrhythmic disorder which is linked to at least 17 genes. The clinical characteristics and genetic mutations may be variable among different population groups and they have not yet been studied in Thai population. Clinical characteristics were retrospectively reviewed from children and young adults with congenital long QT syndrome whose blood samples were sent for genotyping during 1998-2017. Sangers sequencing was used to sequentially identify KCNQ1 or KCNH2 genetic variants. Whole exome sequencing (WES) was used to identify variants in all other known LQTS genes. Of the 20 subjects (17 families), 45% were male, mean QTc was 550.3 ± 68.8 msec (range 470-731 msec) and total Schwartz's score was 5.6 ± 1.2 points (range 3-8 points). Fifty percent of patients had events at rest, 30% had symptoms after adrenergic mediated events, and 20% were asymptomatic. We discovered pathogenic and likely pathogenic genetic variants in KCNQ1, KCNH2, and SCN5A in 6 (35%), 4 (24%), and 2 (12%) families, respectively. One additional patient had variance of unknown significance (VUS) in KCNH2 and another one in ANK2. No pathogenic genetic variant was found in 3 patients (18%). Most patients received beta-blocker and 9 (45%) had ICD implanted. LQT1 patients were either asymptomatic or had stress-induced arrhythmia. Most of the LQT2 and LQT3 patients developed symptoms at rest or during sleep. Our patients with LQTS were mostly symptomatic at presentation. The genetic mutations were predominantly in LQT1, LQT2, and LQT3 genes

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand.

BACKGROUND Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model.OBJECTIVE The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.METHODS We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low frequency variants.RESULTS Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 x 10(-10)). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 x 10(-10)).The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 x 10(-) (9)). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF 0.001 and 0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3).CONCLUSION The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

BACKGROUND: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model. OBJECTIVE: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand. METHODS: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants. RESULTS: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] 0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3). CONCLUSION: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci