This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were Developed in partnership with and endorsed by the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS). Developed in collaboration with and endorsed by the Association for European Cardiovascular Pathology (AECVP), the European Society of Human Genetics (ESHG), the Latin American Heart Rhythm Society (LAHRS), the National Society of Genetic Counselors (NSGC), and the Pediatric and Congenital Electrophysiology Society (PACES). Developed in collaboration with the European Heart Rhythm Association (EHRA). For copies of this document, please contact the Elsevier Inc. Reprint Department
This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
Background Brugada syndrome (BrS) is a sudden arrhythmic death. The prevalence of BrS is higher in the Southeast Asian populations than that in Caucasian patients. A previous genome-wide association study (GWAS) has reported 13 SNPs significantly associated with BrS. However, no study was performed to validate whether these SNPs are enriched in BrS patients in Han Chinese (HC). Purpose Evaluating the common variants previously reported in Caucasian BrS patients could be generalized to HC BrS patients in Taiwan Methods We genotyped 200 unrelated BrS patients using Affymetrix TWB Array (N=653,291 SNPs, a customized array for HC in Taiwan). The controls are obtained from the Taiwan Biobank (N ≈ 16,000) using the same array. An imputation workflow was shown in Figure 1. To confirm the accuracy of the imputed genotype of each variant, Sanger sequencing was performed in 10% of randomly selected cases. Results Among the 3 most important common variants (rs11708996 in SCN5A, rs10428132 in SCN10A and rs9388451 in HEY2/NCOA7) reported in the previous GWAS mainly conducted in Caucasian BrS patients, 2 of them (rs10428132 and rs9388451) were successfully replicated in the HC population in Taiwan (P<0.01). We also found that the differences of minor allele frequency (dMAF: the MAF of cases minus the MAF of controls) of the two variants were relatively smaller between the BrS cases and healthy controls in HC population compared with that in Caucasian populations (dMAF, rs9388451: 0.15 (Caucasian) vs −0.07 (HC); rs10428132: 0.28 (Caucasian) vs 0.11 (HC)). For the remaining 10 common variants reaching genome-wide significance (P=5×10–8) in Caucasian BrS patients, 9 of them were also significantly enriched in the HC BrS patients after the Bonferroni correction (P<0.05/12=0.0042). We next analyzed the variants identified in the previous GWAS on ECG traits (PR interval, QRS duration, QTc interval, and heart rate) in the Caucasian population. Among the reported 75 variants associated with ECG traits, 5 common variants (rs6798015 (PR), rs1760876 (QRS), rs6795970 (PR/QRS), rs2074238 (QTc) and rs314370 (heart rate)) were significant after Bonferroni correction (P<0.05/75=0.00066). Figure 1 Conclusions The preliminary results indicated that 85% of common variants of SCN10A and HEY2/NCOA7 previously reported in Caucasian BrS patients are replicated in BrS patients in the HC population but not the common variant of SCN5A (rs11708996). Furthermore, the common variants of SCN10A and HEY2/NCOA7 related to cardiac depolarization or repolarization may also contribute to the development of BrS. Acknowledgement/Funding NTUH 106-S3469, NTUH106-S3458 and NTUH 106-018
On Behalf SADS-TW BrS registry Background Brugada syndrome (BrS) is an inheritable arrhythmic disease responsible for sudden cardiac death. Information on the prevalence and role of SCN10A variants in BrS is limited and equivocal. Purpose We aimed to investigate the prevalence and role of SCN10A variants in BrS in Han Chinese. Methods From 2000 to 2017, we prospectively and consecutively enrolled 176 unrelated BrS patients from the Han Chinese population in Taiwan (the SADS-TW BrS registry). Thirty-four BrS-related genes were screened by next-generation sequencing, using Taiwan Biobank as the population reference. The pathogenicity was evaluated by literature review and in silico analyses, including the SKAT-O algorithm. Results The SKAT-O algorithm showed that rare variants of SCN10A, but not common variants, were significantly different between BrS patients and healthy controls in the additive and dominant models (p-value <0.001), suggesting that rare SCN10A variants may play a role in BrS. Six likely pathogenic SCN10A variants were found in 6 patients and were compared to 25 pathogenic or likely pathogenic SCN5A variants found in 29 patients. The patients with likely pathogenic SCN10A variants tended to exhibit sudden death in older age and have a shorter QRS interval than those carrying pathogenic or likely pathogenic SCN5A variants or no variants in either gene (p = 0.06, 0.07, respectively). Collectively, the prevalence of likely pathogenic SCN10A variants was 3.4% in Han Chinese patients with BrS in Taiwan. Conclusions SCN10A likely pathogenic variants were present in 3.4% of Han Chinese BrS patients. Rare SCN10A variants may play a role in BrS, and may have impact on clinical and electrocardiographic manifestations. Table 1. Patient Nucleotide Amino acid TWB gnomAD_EA REVEL CADD PHRED SIFT Polyphen-2 GERP++ 1 c.5789A > T p.D1930V 0.001318 0.0008700 0.479 24.5 Damaging Possibly damaging 4.22 2 c.2341G > A p.G781R 0 0.00005301 0.866 33 Damaging Probably damaging 4.83 3 c.5587C > T p.R1863W 0.000502 0 0.832 27.8 Damaging Probably damaging 1.97 4 c.2161C > T p.P721S 0.000989 0.0009016 0.933 28.5 Damaging Probably damaging 4.19 5 c.3749G > A p.R1250Q 0 0 0.907 31 Damaging Probably damaging 4.23 6 c.1825A > T p.R609W 0.000659 0.0001591 0.811 32 Damaging Probably damaging 4.28 Clinical and predicted functional characteristics of 6 likely pathogenic SCN10A variants. EA = East Asian; GERP = Genomic Evolutionary Rate Profiling; TWB = Taiwan Biobank. Transcript: NM_006514.3. Abstract 299 Figure. Location of the SCN10A variants
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