Original Research ARTICLE
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
- 1Department of Internal Medicine, National Taiwan University Hospital, Taiwan
- 2Department of Public Health, National Taiwan University, Taiwan
- 3Lankenau Heart Institute, United States
- 4Lankenau Institute for Medical Research, United States
- 5Sidney Kimmel Medical College (SKMC), United States
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, only 14 (77.8%) were present in the 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.
Keywords: Brugada Syndrome, Sudden cardiac death, Inherited cardiac arrhythmia syndrome, Allele frequency, Pathogenic variants
Received: 14 Sep 2018;
Accepted: 07 Dec 2018.
Edited by:M. Z. A. Bhuiyan, Lausanne University Hospital (CHUV), Switzerland
Reviewed by:Nelson L. Tang, The Chinese University of Hong Kong, China
Apichai Khong, Chulalongkorn University, Thailand
Seiko Ohno, National Cerebral and Cardiovascular Center (Japan), Japan
Copyright: © 2018 Chen, Lu, Lin, Liu, Ho, Huang, Lai, Hwang, Yeh, Wu, Juang and Antzelevitch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: MD, PhD. Jyh-Ming J. Juang, National Taiwan University Hospital, Department of Internal Medicine, Taipei, Taiwan, firstname.lastname@example.org