Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, p < 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, p = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-SCN5A variants, which may be pathogenic in some ancestries but only disease-predisposing in others

Unique clinical characteristics and SCN5A mutations in patients with Brugada syndrome in Taiwan

Brugada syndrome (BrS) is a hereditable sudden cardiac death (SCD). Mutations in the SCN5A gene (the most common BrS-causing gene) are responsible for 20–25% of this disease in Caucasian populations. However, the prevalence of SCN5A mutations in patients with BrS in the Chinese Han population in Taiwan remains unknown. Therefore, in this study, we investigated the prevalence of the SCN5A mutation in the largest BrS cohort in Taiwan. Methods: We consecutively enrolled 47 unrelated patients with BrS from medical centers and hospitals in Taiwan between 2000 and 2010. Mutations within all the 27 translated exons, and exon–intron boundaries of the SCN5A-encoded cardiac sodium channel were screened in all patients with BrS using direct sequencing. A total of 500 unrelated healthy volunteers with a normal electrocardiogram were genotyped as a control group. Results: SCN5A genetic variants were identified in 14 of the 47 patients with BrS and four of the 14 patients with BrS had missense mutations (1651 G>A, 1776 C>G, 3578 G>A). The prevalence rate of SCN5A mutations was approximately 8% (4/47), which was significantly lower than that reported in Caucasian populations (20–25%; p = 0.0007). The average age of these 14 BrS patients with SCN5A variants at diagnosis (12 men and 2 women) was 40 ± 13 years. Four patients experienced SCD, and six presented with seizure or syncope. Only three patients (3/14, 21.4%) had a family history of SCD. Conclusion: The prevalence of SCN5A mutations in the Chinese Han population in Taiwan may be lower than that reported in the Caucasian populations. In addition, most patients with BrS did not have a family history of SCD

Comparisons of clinical impacts on individuals with Brugada electrocardiographic patterns defined by ISHNE criteria or EHRA/HRS/APHRS criteria: a nationwide community-based study

<p><b>Introduction:</b> Identifying Brugada electrocardiographic pattern (BrP) early is crucial to prevent sudden cardiac death. Two different diagnostic criteria proposed by International Society for Holter and Noninvasive Electrocardiography (ISHNE) and Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society (HRS/EHRA/APHRS) were widely used in clinical practice. The difference in prevalence and prognosis of BrP by applying the two different criteria was never studied before.</p> <p><b>Methods:</b> This study was prospectively conducted in a nationwide large-scale stratified random sampling community-based cohort (HALST) from Han Chinese population in Taiwan from December 2008 to December 2012. We compared the prevalence and prognosis of BrP defined by the two diagnostic criteria.</p> <p><b>Results:</b> A total of 5214 adults were enrolled (2530 men) with mean age of 69.3 years. Four had spontaneous type 1 BrP (0.077%). By the HRS/EHRA/APHRS criteria, 68 individuals have type 2 BrP (1.30%) and 101 have type 3 BrP (1.94%) whereas by the ISHNE criteria, 46 individuals exhibited type 2 BrP (0.88%). When applying the ISHNE criteria, the number of individuals with BrP decreased by 71%. However, all-cause mortality and cardiovascular mortality were not different between individuals with or without BrP, irrespective of the criteria used.</p> <p><b>Conclusions:</b> The two different criteria may impact the diagnostic yield of individuals with BrP, but do not affect the prognosis of the individuals with BrP.Key messages</p><p>Comparing with the use of HRS/EHRA/APHRS criteria, the number of individuals with Brugada ECG patterns was decreased by 71% when applying the ISHNE criteria.</p><p>The prognosis of individuals with Brugada ECG patterns defined by 2012 ISHNE or 2013 HRS/EHRA/APHRS criteria were not different.</p><p></p> <p>Comparing with the use of HRS/EHRA/APHRS criteria, the number of individuals with Brugada ECG patterns was decreased by 71% when applying the ISHNE criteria.</p> <p>The prognosis of individuals with Brugada ECG patterns defined by 2012 ISHNE or 2013 HRS/EHRA/APHRS criteria were not different.</p

Comparisons of clinical impacts on individuals with Brugada electrocardiographic patterns defined by ISHNE criteria or EHRA/HRS/APHRS criteria: A nationwide community-based study

[[abstract]]INTRODUCTION: Identifying Brugada electrocardiographic pattern (BrP) early is crucial to prevent sudden cardiac death. Two different diagnostic criteria proposed by International Society for Holter and Noninvasive Electrocardiography (ISHNE) and Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society (HRS/EHRA/APHRS) were widely used in clinical practice. The difference in prevalence and prognosis of BrP by applying the two different criteria was never studied before. METHODS: This study was prospectively conducted in a nationwide large-scale stratified random sampling community-based cohort (HALST) from Han Chinese population in Taiwan from December 2008 to December 2012. We compared the prevalence and prognosis of BrP defined by the two diagnostic criteria. RESULTS: A total of 5214 adults were enrolled (2530 men) with mean age of 69.3 years. Four had spontaneous type 1 BrP (0.077%). By the HRS/EHRA/APHRS criteria, 68 individuals have type 2 BrP (1.30%) and 101 have type 3 BrP (1.94%) whereas by the ISHNE criteria, 46 individuals exhibited type 2 BrP (0.88%). When applying the ISHNE criteria, the number of individuals with BrP decreased by 71%. However, all-cause mortality and cardiovascular mortality were not different between individuals with or without BrP, irrespective of the criteria used. CONCLUSIONS: The two different criteria may impact the diagnostic yield of individuals with BrP, but do not affect the prognosis of the individuals with BrP. Key messages Comparing with the use of HRS/EHRA/APHRS criteria, the number of individuals with Brugada ECG patterns was decreased by 71% when applying the ISHNE criteria. The prognosis of individuals with Brugada ECG patterns defined by 2012 ISHNE or 2013 HRS/EHRA/APHRS criteria were not different