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1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants
BACKGROUND: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in t...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354277/ https://www.ncbi.nlm.nih.gov/pubmed/35932045 http://dx.doi.org/10.1186/s40246-022-00402-2 |
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author | Bajaj, Anjali Senthivel, Vigneshwar Bhoyar, Rahul Jain, Abhinav Imran, Mohamed Rophina, Mercy Divakar, Mohit Kumar Jolly, Bani Verma, Ankit Mishra, Anushree Sharma, Disha Deepti, Siddharthan Sharma, Gautam Bansal, Raghav Yadav, Rakesh Scaria, Vinod Naik, Nitish Sivasubbu, Sridhar |
author_facet | Bajaj, Anjali Senthivel, Vigneshwar Bhoyar, Rahul Jain, Abhinav Imran, Mohamed Rophina, Mercy Divakar, Mohit Kumar Jolly, Bani Verma, Ankit Mishra, Anushree Sharma, Disha Deepti, Siddharthan Sharma, Gautam Bansal, Raghav Yadav, Rakesh Scaria, Vinod Naik, Nitish Sivasubbu, Sridhar |
author_sort | Bajaj, Anjali |
collection | PubMed |
description | BACKGROUND: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. RESULTS: We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. CONCLUSION: A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9–1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-022-00402-2. |
format | Online Article Text |
id | pubmed-9354277 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-93542772022-08-06 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants Bajaj, Anjali Senthivel, Vigneshwar Bhoyar, Rahul Jain, Abhinav Imran, Mohamed Rophina, Mercy Divakar, Mohit Kumar Jolly, Bani Verma, Ankit Mishra, Anushree Sharma, Disha Deepti, Siddharthan Sharma, Gautam Bansal, Raghav Yadav, Rakesh Scaria, Vinod Naik, Nitish Sivasubbu, Sridhar Hum Genomics Research BACKGROUND: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. RESULTS: We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. CONCLUSION: A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9–1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-022-00402-2. BioMed Central 2022-08-05 /pmc/articles/PMC9354277/ /pubmed/35932045 http://dx.doi.org/10.1186/s40246-022-00402-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Bajaj, Anjali Senthivel, Vigneshwar Bhoyar, Rahul Jain, Abhinav Imran, Mohamed Rophina, Mercy Divakar, Mohit Kumar Jolly, Bani Verma, Ankit Mishra, Anushree Sharma, Disha Deepti, Siddharthan Sharma, Gautam Bansal, Raghav Yadav, Rakesh Scaria, Vinod Naik, Nitish Sivasubbu, Sridhar 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title | 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title_full | 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title_fullStr | 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title_full_unstemmed | 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title_short | 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants |
title_sort | 1029 genomes of self-declared healthy individuals from india reveal prevalent and clinically relevant cardiac ion channelopathy variants |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354277/ https://www.ncbi.nlm.nih.gov/pubmed/35932045 http://dx.doi.org/10.1186/s40246-022-00402-2 |
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