伦敦大学学院Damian Smedley小组揭示了100,000基因组计划中罕见疾病基因关联。该项研究成果发表在2025年2月26日出版的《自然》上。

为了寻找这种关联，课题组研究人员开发了孟德尔疾病罕见变异基因负担分析框架，并将其应用于100,000基因组计划招募的34,851例患者及其家庭成员的全基因组测序中的蛋白质编码变异。总共发现了141种新的关联，其中5种是最近发表的独立疾病基因证据。经过计算机分类和临床专家审查，69个关联被优先考虑，其中30个可以与现有的实验证据相关联。总体遗传和实验证据最强的五个相关性是单基因糖尿病与已知的β细胞调节因子UNC13A，精神分裂症与GPR17，癫痫与RBFOX3， charco - marie - tooth病与ARPC3和前节眼异常与POMK。进一步确认这些和其他关联可能会导致更多的诊断，强调大规模统计方法对罕见病基因关联发现的临床影响。

据了解，高达80%的罕见病患者在基因组测序后仍未得到诊断，其中许多可能涉及尚未发现的疾病-基因关联的致病性变异。

附：英文原文

Title: Rare disease gene association discovery in the 100,000 Genomes Project

Author: Cipriani, Valentina, Vestito, Letizia, Magavern, Emma F., Jacobsen, Julius O. B., Arno, Gavin, Behr, Elijah R., Benson, Katherine A., Bertoli, Marta, Bockenhauer, Detlef, Bowl, Michael R., Burley, Kate, Chan, Li F., Chinnery, Patrick, Conlon, Peter J., Costa, Marcos A., Davidson, Alice E., Dawson, Sally J., Elhassan, Elhussein A. E., Flanagan, Sarah E., Futema, Marta, Gale, Daniel P., Garca-Ruiz, Sonia, Corcia, Cecilia Gonzalez, Griffin, Helen R., Hambleton, Sophie, Hicks, Amy R., Houlden, Henry, Houlston, Richard S., Howles, Sarah A., Kleta, Robert, Lekkerkerker, Iris, Lin, Siying, Liskova, Petra, Mitchison, Hannah H., Morsy, Heba, Mumford, Andrew D., Newman, William G., Neatu, Ruxandra, OToole, Edel A., Ong, Albert C. M., Pagnamenta, Alistair T., Rahman, Shamima, Rajan, Neil, Robinson, Peter N., Ryten, Mina, Sadeghi-Alavijeh, Omid, Sayer, John A., Shovlin, Claire L., Taylor, Jenny C., Teltsh, Omri, Tomlinson, Ian, Tucci, Arianna, Turnbull, Clare, van Eerde, Albertien M., Ware, James S., Watts, Laura M., Webster, Andrew R., Westbury, Sarah K., Zheng, Sean L.

Issue&Volume: 2025-02-26

Abstract: Up to 80% of rare disease patients remain undiagnosed after genomic sequencing, with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project. A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot–Marie–Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease–gene association discovery.

DOI: 10.1038/s41586-025-08623-w

Source: https://www.nature.com/articles/s41586-025-08623-w

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html