Illumina SNP array data for Brugdata syndrome patients in Taiwan

Background Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant. Findings A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P<0.001; OR: 1.76 (1.02–3.05), P = 0.04, respectively). Interpretation This GSTM3 deletion is frequently observed in BrS patients and is associated with reduced INa, pointing to this as a novel potential genetic modifier/risk predictor for the development of the electrocardiographic and arrhythmic manifestations of BrS. We consecutively recruited 335 unrelated patients with BrS from 2000 to 2018 in the Taiwanese population in Taiwan; 76 were identified via symptoms of sudden cardiac arrest (SCA) or syncope early in the study period (2000–2010) and 259 more, both symptomatic and asymptomatic, were identified later (2011–2018), after the SADS-TW BrS registry increased awareness of BrS. borigines were excluded from this study. BrS was diagnosed by 2 independent cardiologists using established criteria (Shanghai BrS Score ≥ 3.5). Peripheral blood samples were collected from all participants.Omni1-Quad BeadChip microarrays (Illumina, USA) were performed according to the manufacturer's instructions.