Burden of Mendelian disorders in a large Middle Eastern biobank

<h3>Background</h3><p dir="ltr">Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.</p><h3>M...

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التفاصيل البيبلوغرافية
المؤلف الرئيسي:	Waleed Aamer (14056969) (author)
مؤلفون آخرون:	Aljazi Al-Maraghi (14056975) (author), Najeeb Syed (12561967) (author), Geethanjali Devadoss Gandhi (14056966) (author), Elbay Aliyev (14056972) (author), Alya A. Al-Kurbi (18324927) (author), Omayma Al-Saei (18288931) (author), Muhammad Kohailan (748774) (author), Navaneethakrishnan Krishnamoorthy (391608) (author), Sasirekha Palaniswamy (14152563) (author), Khulod Al-Malki (18324930) (author), Saleha Abbasi (18324933) (author), Nourhen Agrebi (14151222) (author), Fatemeh Abbaszadeh (13841344) (author), Ammira S. Al-Shabeeb Akil (15376391) (author), Ramin Badii (491543) (author), Tawfeg Ben-Omran (6663634) (author), Bernice Lo (3441317) (author), Said I. Ismail (11721428) (author), Wadha Al-Muftah (14152551) (author), Radja Badji (14152548) (author), Hamdi Mbarek (134997) (author), Dima Darwish (14152545) (author), Tasnim Fadl (14152533) (author), Heba Yasin (14152542) (author), Maryem Ennaifar (14778556) (author), Rania Abdellatif (18589450) (author), Fatima Alkuwari (14778562) (author), Muhammad Alvi (4831311) (author), Yasser Al-Sarraj (11721425) (author), Chadi Saad (5369351) (author), Asmaa Althani (499903) (author), Eleni Fethnou (14778568) (author), Fatima Qafoud (14778571) (author), Eiman Alkhayat (14778574) (author), Nahla Afifi (193245) (author), Sara Tomei (3441323) (author), Wei Liu (20030) (author), Kun Wang (134525) (author), Stephan Lorenz (466378) (author), Hakeem Almabrazi (6561371) (author), Fazulur Rehaman Vempalli (14778577) (author), Ramzi Temanni (671528) (author), Tariq Abu Saqri (14778580) (author), Mohammedhusen Khatib (14778583) (author), Mehshad Hamza (14778586) (author), Tariq Abu Zaid (14778589) (author), Ahmed El Khouly (19325653) (author), Tushar Pathare (14778595) (author), Shafeeq Poolat (14778598) (author), Rashid Al-Ali (846229) (author), Omar Albagha (8977856) (author), Souhaila Al-Khodor (247417) (author), Mashael Alshafai (14778607) (author), Lotfi Chouchane (61840) (author), Xavier Estivill (23803) (author), Jithesh V. Puthen (14778610) (author), Karsten Suhre (67967) (author), Zohreh Tatari (14778613) (author), Younes Mokrab (6367) (author), Khalid A. Fakhro (3158862) (author), The Qatar Genome Program Research Consortium (14778616) (author)
منشور في:	2024
الموضوعات:	Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Mendelian disorders Rare genetic disease Genome sequencing Consanguinity Qatar Middle East Biobank Arab population Pathogenic variants
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_version_	1864513509726879744
author	Waleed Aamer (14056969)
author2	Aljazi Al-Maraghi (14056975) Najeeb Syed (12561967) Geethanjali Devadoss Gandhi (14056966) Elbay Aliyev (14056972) Alya A. Al-Kurbi (18324927) Omayma Al-Saei (18288931) Muhammad Kohailan (748774) Navaneethakrishnan Krishnamoorthy (391608) Sasirekha Palaniswamy (14152563) Khulod Al-Malki (18324930) Saleha Abbasi (18324933) Nourhen Agrebi (14151222) Fatemeh Abbaszadeh (13841344) Ammira S. Al-Shabeeb Akil (15376391) Ramin Badii (491543) Tawfeg Ben-Omran (6663634) Bernice Lo (3441317) Said I. Ismail (11721428) Wadha Al-Muftah (14152551) Radja Badji (14152548) Hamdi Mbarek (134997) Dima Darwish (14152545) Tasnim Fadl (14152533) Heba Yasin (14152542) Maryem Ennaifar (14778556) Rania Abdellatif (18589450) Fatima Alkuwari (14778562) Muhammad Alvi (4831311) Yasser Al-Sarraj (11721425) Chadi Saad (5369351) Asmaa Althani (499903) Eleni Fethnou (14778568) Fatima Qafoud (14778571) Eiman Alkhayat (14778574) Nahla Afifi (193245) Sara Tomei (3441323) Wei Liu (20030) Kun Wang (134525) Stephan Lorenz (466378) Hakeem Almabrazi (6561371) Fazulur Rehaman Vempalli (14778577) Ramzi Temanni (671528) Tariq Abu Saqri (14778580) Mohammedhusen Khatib (14778583) Mehshad Hamza (14778586) Tariq Abu Zaid (14778589) Ahmed El Khouly (19325653) Tushar Pathare (14778595) Shafeeq Poolat (14778598) Rashid Al-Ali (846229) Omar Albagha (8977856) Souhaila Al-Khodor (247417) Mashael Alshafai (14778607) Lotfi Chouchane (61840) Xavier Estivill (23803) Jithesh V. Puthen (14778610) Karsten Suhre (67967) Zohreh Tatari (14778613) Younes Mokrab (6367) Khalid A. Fakhro (3158862) The Qatar Genome Program Research Consortium (14778616)
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
author_facet	Waleed Aamer (14056969) Aljazi Al-Maraghi (14056975) Najeeb Syed (12561967) Geethanjali Devadoss Gandhi (14056966) Elbay Aliyev (14056972) Alya A. Al-Kurbi (18324927) Omayma Al-Saei (18288931) Muhammad Kohailan (748774) Navaneethakrishnan Krishnamoorthy (391608) Sasirekha Palaniswamy (14152563) Khulod Al-Malki (18324930) Saleha Abbasi (18324933) Nourhen Agrebi (14151222) Fatemeh Abbaszadeh (13841344) Ammira S. Al-Shabeeb Akil (15376391) Ramin Badii (491543) Tawfeg Ben-Omran (6663634) Bernice Lo (3441317) Said I. Ismail (11721428) Wadha Al-Muftah (14152551) Radja Badji (14152548) Hamdi Mbarek (134997) Dima Darwish (14152545) Tasnim Fadl (14152533) Heba Yasin (14152542) Maryem Ennaifar (14778556) Rania Abdellatif (18589450) Fatima Alkuwari (14778562) Muhammad Alvi (4831311) Yasser Al-Sarraj (11721425) Chadi Saad (5369351) Asmaa Althani (499903) Eleni Fethnou (14778568) Fatima Qafoud (14778571) Eiman Alkhayat (14778574) Nahla Afifi (193245) Sara Tomei (3441323) Wei Liu (20030) Kun Wang (134525) Stephan Lorenz (466378) Hakeem Almabrazi (6561371) Fazulur Rehaman Vempalli (14778577) Ramzi Temanni (671528) Tariq Abu Saqri (14778580) Mohammedhusen Khatib (14778583) Mehshad Hamza (14778586) Tariq Abu Zaid (14778589) Ahmed El Khouly (19325653) Tushar Pathare (14778595) Shafeeq Poolat (14778598) Rashid Al-Ali (846229) Omar Albagha (8977856) Souhaila Al-Khodor (247417) Mashael Alshafai (14778607) Lotfi Chouchane (61840) Xavier Estivill (23803) Jithesh V. Puthen (14778610) Karsten Suhre (67967) Zohreh Tatari (14778613) Younes Mokrab (6367) Khalid A. Fakhro (3158862) The Qatar Genome Program Research Consortium (14778616)
author_role	author
dc.creator.none.fl_str_mv	Waleed Aamer (14056969) Aljazi Al-Maraghi (14056975) Najeeb Syed (12561967) Geethanjali Devadoss Gandhi (14056966) Elbay Aliyev (14056972) Alya A. Al-Kurbi (18324927) Omayma Al-Saei (18288931) Muhammad Kohailan (748774) Navaneethakrishnan Krishnamoorthy (391608) Sasirekha Palaniswamy (14152563) Khulod Al-Malki (18324930) Saleha Abbasi (18324933) Nourhen Agrebi (14151222) Fatemeh Abbaszadeh (13841344) Ammira S. Al-Shabeeb Akil (15376391) Ramin Badii (491543) Tawfeg Ben-Omran (6663634) Bernice Lo (3441317) Said I. Ismail (11721428) Wadha Al-Muftah (14152551) Radja Badji (14152548) Hamdi Mbarek (134997) Dima Darwish (14152545) Tasnim Fadl (14152533) Heba Yasin (14152542) Maryem Ennaifar (14778556) Rania Abdellatif (18589450) Fatima Alkuwari (14778562) Muhammad Alvi (4831311) Yasser Al-Sarraj (11721425) Chadi Saad (5369351) Asmaa Althani (499903) Eleni Fethnou (14778568) Fatima Qafoud (14778571) Eiman Alkhayat (14778574) Nahla Afifi (193245) Sara Tomei (3441323) Wei Liu (20030) Kun Wang (134525) Stephan Lorenz (466378) Hakeem Almabrazi (6561371) Fazulur Rehaman Vempalli (14778577) Ramzi Temanni (671528) Tariq Abu Saqri (14778580) Mohammedhusen Khatib (14778583) Mehshad Hamza (14778586) Tariq Abu Zaid (14778589) Ahmed El Khouly (19325653) Tushar Pathare (14778595) Shafeeq Poolat (14778598) Rashid Al-Ali (846229) Omar Albagha (8977856) Souhaila Al-Khodor (247417) Mashael Alshafai (14778607) Lotfi Chouchane (61840) Xavier Estivill (23803) Jithesh V. Puthen (14778610) Karsten Suhre (67967) Zohreh Tatari (14778613) Younes Mokrab (6367) Khalid A. Fakhro (3158862) The Qatar Genome Program Research Consortium (14778616)
dc.date.none.fl_str_mv	2024-04-08T03:00:00Z
dc.identifier.none.fl_str_mv	10.1186/s13073-024-01307-6
dc.relation.none.fl_str_mv	https://figshare.com/articles/journal_contribution/Burden_of_Mendelian_disorders_in_a_large_Middle_Eastern_biobank/26490925
dc.rights.none.fl_str_mv	CC BY 4.0 info:eu-repo/semantics/openAccess
dc.subject.none.fl_str_mv	Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Mendelian disorders Rare genetic disease Genome sequencing Consanguinity Qatar Middle East Biobank Arab population Pathogenic variants
dc.title.none.fl_str_mv	Burden of Mendelian disorders in a large Middle Eastern biobank
dc.type.none.fl_str_mv	Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal
description	<h3>Background</h3><p dir="ltr">Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.</p><h3>Methods</h3><p dir="ltr">Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.</p><h3>Results</h3><p dir="ltr">We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.</p><h3>Conclusions</h3><p dir="ltr">This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.</p><h2>Other Information</h2><p dir="ltr">Published in: Genome Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13073-024-01307-6" target="_blank">https://dx.doi.org/10.1186/s13073-024-01307-6</a></p>
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identifier_str_mv	10.1186/s13073-024-01307-6
network_acronym_str	Manara2
network_name_str	Manara2
oai_identifier_str	oai:figshare.com:article/26490925
publishDate	2024
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rights_invalid_str_mv	CC BY 4.0
spelling	Burden of Mendelian disorders in a large Middle Eastern biobankWaleed Aamer (14056969)Aljazi Al-Maraghi (14056975)Najeeb Syed (12561967)Geethanjali Devadoss Gandhi (14056966)Elbay Aliyev (14056972)Alya A. Al-Kurbi (18324927)Omayma Al-Saei (18288931)Muhammad Kohailan (748774)Navaneethakrishnan Krishnamoorthy (391608)Sasirekha Palaniswamy (14152563)Khulod Al-Malki (18324930)Saleha Abbasi (18324933)Nourhen Agrebi (14151222)Fatemeh Abbaszadeh (13841344)Ammira S. Al-Shabeeb Akil (15376391)Ramin Badii (491543)Tawfeg Ben-Omran (6663634)Bernice Lo (3441317)Said I. Ismail (11721428)Wadha Al-Muftah (14152551)Radja Badji (14152548)Hamdi Mbarek (134997)Dima Darwish (14152545)Tasnim Fadl (14152533)Heba Yasin (14152542)Maryem Ennaifar (14778556)Rania Abdellatif (18589450)Fatima Alkuwari (14778562)Muhammad Alvi (4831311)Yasser Al-Sarraj (11721425)Chadi Saad (5369351)Asmaa Althani (499903)Eleni Fethnou (14778568)Fatima Qafoud (14778571)Eiman Alkhayat (14778574)Nahla Afifi (193245)Sara Tomei (3441323)Wei Liu (20030)Kun Wang (134525)Stephan Lorenz (466378)Hakeem Almabrazi (6561371)Fazulur Rehaman Vempalli (14778577)Ramzi Temanni (671528)Tariq Abu Saqri (14778580)Mohammedhusen Khatib (14778583)Mehshad Hamza (14778586)Tariq Abu Zaid (14778589)Ahmed El Khouly (19325653)Tushar Pathare (14778595)Shafeeq Poolat (14778598)Rashid Al-Ali (846229)Omar Albagha (8977856)Souhaila Al-Khodor (247417)Mashael Alshafai (14778607)Lotfi Chouchane (61840)Xavier Estivill (23803)Jithesh V. Puthen (14778610)Karsten Suhre (67967)Zohreh Tatari (14778613)Younes Mokrab (6367)Khalid A. Fakhro (3158862)The Qatar Genome Program Research Consortium (14778616)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesMendelian disordersRare genetic diseaseGenome sequencingConsanguinityQatarMiddle EastBiobankArab populationPathogenic variants<h3>Background</h3><p dir="ltr">Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.</p><h3>Methods</h3><p dir="ltr">Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.</p><h3>Results</h3><p dir="ltr">We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.</p><h3>Conclusions</h3><p dir="ltr">This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.</p><h2>Other Information</h2><p dir="ltr">Published in: Genome Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13073-024-01307-6" target="_blank">https://dx.doi.org/10.1186/s13073-024-01307-6</a></p>2024-04-08T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s13073-024-01307-6https://figshare.com/articles/journal_contribution/Burden_of_Mendelian_disorders_in_a_large_Middle_Eastern_biobank/26490925CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/264909252024-04-08T03:00:00Z
spellingShingle	Burden of Mendelian disorders in a large Middle Eastern biobank Waleed Aamer (14056969) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Mendelian disorders Rare genetic disease Genome sequencing Consanguinity Qatar Middle East Biobank Arab population Pathogenic variants
status_str	publishedVersion
title	Burden of Mendelian disorders in a large Middle Eastern biobank
title_full	Burden of Mendelian disorders in a large Middle Eastern biobank
title_fullStr	Burden of Mendelian disorders in a large Middle Eastern biobank
title_full_unstemmed	Burden of Mendelian disorders in a large Middle Eastern biobank
title_short	Burden of Mendelian disorders in a large Middle Eastern biobank
title_sort	Burden of Mendelian disorders in a large Middle Eastern biobank
topic	Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Mendelian disorders Rare genetic disease Genome sequencing Consanguinity Qatar Middle East Biobank Arab population Pathogenic variants

Burden of Mendelian disorders in a large Middle Eastern biobank

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