Lama AlAbdi, Sateesh Maddirevula, Bayan Aljamal, Halima Hamid, Aisha Almulhim, Mais O Hashem, Yusra Algoos, Mashael Alqahtani, Shahad Albaloshi, Mohammed Alghamdi, Mohammed Alduaylij, Hanan E Shamseldin, Seba Nadeef, Nisha Patel, Firdous Abdulwahab, Omar Abouyousef, Tarfa Alshidi, Amal Jaafar, Mohamed Abouelhoda, Adel Alhazzani, Ahmed Alfares, Ahmad Qudair, Ahood Alsulaiman, Amal Alhashem, Arif O Khan, Aziza Chedrawi, Basel Alebdi, Fahad AlAjlan, Fawaz Alotaibi, Hamad Alzaidan, Hanaa Banjar, Hanem Abdelraouf, Hisham Alkuraya, Iman Abumansour, Khowlah Alfayez, Maha Tulbah, Mohammed Alowain, Mohammed Alqahtani, Mohammed El-Kalioby, Mohammad Shboul, Raashda Sulaiman, Saed Al Tala, Sameena Khan, Serdar Coskun, Sobaihi Mrouge, Walaa Alenazi, Zuhair Rahbeeni, Fowzan S Alkuraya
{"title":"Arab founder variants: Contributions to clinical genomics and precision medicine.","authors":"Lama AlAbdi, Sateesh Maddirevula, Bayan Aljamal, Halima Hamid, Aisha Almulhim, Mais O Hashem, Yusra Algoos, Mashael Alqahtani, Shahad Albaloshi, Mohammed Alghamdi, Mohammed Alduaylij, Hanan E Shamseldin, Seba Nadeef, Nisha Patel, Firdous Abdulwahab, Omar Abouyousef, Tarfa Alshidi, Amal Jaafar, Mohamed Abouelhoda, Adel Alhazzani, Ahmed Alfares, Ahmad Qudair, Ahood Alsulaiman, Amal Alhashem, Arif O Khan, Aziza Chedrawi, Basel Alebdi, Fahad AlAjlan, Fawaz Alotaibi, Hamad Alzaidan, Hanaa Banjar, Hanem Abdelraouf, Hisham Alkuraya, Iman Abumansour, Khowlah Alfayez, Maha Tulbah, Mohammed Alowain, Mohammed Alqahtani, Mohammed El-Kalioby, Mohammad Shboul, Raashda Sulaiman, Saed Al Tala, Sameena Khan, Serdar Coskun, Sobaihi Mrouge, Walaa Alenazi, Zuhair Rahbeeni, Fowzan S Alkuraya","doi":"10.1016/j.medj.2024.10.005","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities.</p><p><strong>Methods: </strong>Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome.</p><p><strong>Findings: </strong>Strikingly, ∼34% of Arab founder variants are absent in gnomAD. We found a strong contribution of Arab founder variants to the identification of novel gene-disease links (n = 224) and the support/dispute (n = 81 support, n = 101 dispute) of previously reported candidate gene-disease links. The powerful segregation evidence generated by Arab founder variants allowed many ClinVar and Human Gene Mutation Database variants to be reclassified. Overall, 39.5% of diagnostic reports from our clinical lab are based on founder variants, and 19.41% of tested individuals carry at least one pathogenic founder variant. The presumptive loss-of-function mechanism that typically underlies autosomal recessive diseases means that Arab founder variants also offer unique opportunities in \"druggable genome\" research. Arab founder variants were also informative of migration patterns in the Middle East consistent with documented historical accounts.</p><p><strong>Conclusions: </strong>We highlight the contribution of founder variants from an under-represented population group to precision medicine and inform future prevention programs. Our study also sheds light on the added value of these variants in supplementing other lines of research in tracing population history.</p><p><strong>Funding: </strong>There is no funding for this work.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.10.005","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities.
Methods: Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome.
Findings: Strikingly, ∼34% of Arab founder variants are absent in gnomAD. We found a strong contribution of Arab founder variants to the identification of novel gene-disease links (n = 224) and the support/dispute (n = 81 support, n = 101 dispute) of previously reported candidate gene-disease links. The powerful segregation evidence generated by Arab founder variants allowed many ClinVar and Human Gene Mutation Database variants to be reclassified. Overall, 39.5% of diagnostic reports from our clinical lab are based on founder variants, and 19.41% of tested individuals carry at least one pathogenic founder variant. The presumptive loss-of-function mechanism that typically underlies autosomal recessive diseases means that Arab founder variants also offer unique opportunities in "druggable genome" research. Arab founder variants were also informative of migration patterns in the Middle East consistent with documented historical accounts.
Conclusions: We highlight the contribution of founder variants from an under-represented population group to precision medicine and inform future prevention programs. Our study also sheds light on the added value of these variants in supplementing other lines of research in tracing population history.
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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