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Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs

BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. METHODS: Here, we established th...

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Autores principales: Al‐Shafai, Kholoud N., Al‐Hashemi, Mohammed, Manickam, Chidambaram, Musa, Rania, Selvaraj, Senthil, Syed, Najeeb, Vempalli, Fazulur, Ali, Muneera, Yacoub, Magdi, Estivill, Xavier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372065/
https://www.ncbi.nlm.nih.gov/pubmed/34137518
http://dx.doi.org/10.1002/mgg3.1709
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author Al‐Shafai, Kholoud N.
Al‐Hashemi, Mohammed
Manickam, Chidambaram
Musa, Rania
Selvaraj, Senthil
Syed, Najeeb
Vempalli, Fazulur
Ali, Muneera
Yacoub, Magdi
Estivill, Xavier
author_facet Al‐Shafai, Kholoud N.
Al‐Hashemi, Mohammed
Manickam, Chidambaram
Musa, Rania
Selvaraj, Senthil
Syed, Najeeb
Vempalli, Fazulur
Ali, Muneera
Yacoub, Magdi
Estivill, Xavier
author_sort Al‐Shafai, Kholoud N.
collection PubMed
description BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. METHODS: Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. RESULTS: In HCM, the analysis of 25 HCM‐associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes. CONCLUSION: We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants.
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spelling pubmed-83720652021-08-23 Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs Al‐Shafai, Kholoud N. Al‐Hashemi, Mohammed Manickam, Chidambaram Musa, Rania Selvaraj, Senthil Syed, Najeeb Vempalli, Fazulur Ali, Muneera Yacoub, Magdi Estivill, Xavier Mol Genet Genomic Med Original Articles BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. METHODS: Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. RESULTS: In HCM, the analysis of 25 HCM‐associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes. CONCLUSION: We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants. John Wiley and Sons Inc. 2021-06-17 /pmc/articles/PMC8372065/ /pubmed/34137518 http://dx.doi.org/10.1002/mgg3.1709 Text en © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Al‐Shafai, Kholoud N.
Al‐Hashemi, Mohammed
Manickam, Chidambaram
Musa, Rania
Selvaraj, Senthil
Syed, Najeeb
Vempalli, Fazulur
Ali, Muneera
Yacoub, Magdi
Estivill, Xavier
Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title_full Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title_fullStr Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title_full_unstemmed Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title_short Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs
title_sort genetic evaluation of cardiomyopathies in qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the arabs
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372065/
https://www.ncbi.nlm.nih.gov/pubmed/34137518
http://dx.doi.org/10.1002/mgg3.1709
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