AlAbdi Lama, Maddirevula Sateesh, Aljamal Bayan, Hamid Halima, Almulhim Aisha, Hashem Mais O, Algoos Yusra, Alqahtani Mashael, Albaloshi Shahad, Alghamdi Mohammed, Alduaylij Mohammed, Shamseldin Hanan E, Nadeef Seba, Patel Nisha, Abdulwahab Firdous, Abouyousef Omar, Alshidi Tarfa, Jaafar Amal, Abouelhoda Mohamed, Alhazzani Adel, Alfares Ahmed, Qudair Ahmad, Alsulaiman Ahood, Alhashem Amal, Khan Arif O, Chedrawi Aziza, Alebdi Basel, AlAjlan Fahad, Alotaibi Fawaz, Alzaidan Hamad, Banjar Hanaa, Abdelraouf Hanem, Alkuraya Hisham, Abumansour Iman, Alfayez Khowlah, Tulbah Maha, Alowain Mohammed, Alqahtani Mohammed, El-Kalioby Mohammed, Shboul Mohammad, Sulaiman Raashda, Al Tala Saed, Khan Sameena, Coskun Serdar, Mrouge Sobaihi, Alenazi Walaa, Rahbeeni Zuhair, Alkuraya Fowzan S
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
Department of Clinical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
Med. 2025 Mar 14;6(3):100528. doi: 10.1016/j.medj.2024.10.005. Epub 2024 Nov 5.
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.
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.
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.
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.
There is no funding for this work.
奠基者变异是指不具有密切亲缘关系的个体所共有的祖先变异。其中一些变异在孟德尔疾病背景下具有较大效应大小，为精准医学提供了众多机会。
利用中东地区最大的孟德尔疾病数据集之一，我们从18360个外显子组和基因组中鉴定出2908个与医学相关的奠基者变异，并研究了它们对人类基因组临床注释的贡献。
令人惊讶的是，gnomAD数据库中不存在约34%的阿拉伯奠基者变异。我们发现阿拉伯奠基者变异对鉴定新的基因-疾病关联（n = 224）以及支持/质疑先前报道的候选基因-疾病关联（n = 81个支持，n = 101个质疑）有很大贡献。阿拉伯奠基者变异产生的有力分离证据使得许多ClinVar和人类基因突变数据库中的变异得以重新分类。总体而言，我们临床实验室39.5%的诊断报告基于奠基者变异，19.41%的受测个体携带至少一种致病的奠基者变异。常染色体隐性疾病通常所基于的推定功能丧失机制意味着阿拉伯奠基者变异在“可药物基因组”研究中也提供了独特的机会。阿拉伯奠基者变异还揭示了与有记录的历史记载一致的中东地区人口迁移模式。
我们强调了来自代表性不足人群组的奠基者变异对精准医学的贡献，并为未来的预防计划提供了信息。我们的研究还揭示了这些变异在补充其他追踪人口历史研究方面的附加价值。
本研究无资金支持。
