ABSTRACT
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. FUNDING: This work was supported by the Ministry of Science and Technology (107-2314-B-002-261-MY3 to J.M.J. Juang), and by grants HL47678, HL138103 and HL152201 from the National Institutes of Health to CA.
ABSTRACT
Aggressive tracing of contacts of confirmed cases is crucial to Taiwan's successful control of the early spread of COVID-19. As the pandemic lingers, an epidemiological investigation that can be conducted efficiently in a timely manner can help decrease the burden on the health personnel and increase the usefulness of such information in decision making. To develop a new tool that can improve the current practice of epidemiological investigation by incorporating new technologies in digital platform and knowledge graphs. To meet the various needs of the epidemiological investigation, we decided to develop an e-Outbreak Platform that provides a semi-structured, multifaceted, computer-aided questionnaire for outbreak investigation. There are three major parts of the platform: (1) a graphic portal that allows users to have an at-glance grasp of the functions provided by the platform and then choose the one they need; (2) disease-specific questionnaires that can accommodate different formats of the information, including text typing, button selection, and pull-down menu; and (3) functions to utilize the stored information, including report generation, statistical analyses, and knowledge graphs displaying contact tracing. When the number of outbreak investigation increases, the knowledge graphs can be extended to encompass other persons appearing in the same location at the same time, i.e., constituting a potential contact cluster. The information extracted can also be used to display the tracing on a map in animation. Overall, this system can provide a basis for further refinement that can be generalized to a variety of outbreak investigations.