Jackson Adam, Thaker Nishi, Blakes Alexander, Rice Gillian, Griffiths-Jones Sam, Balasubramanian Meena, Campbell Jennifer, Shannon Nora, Choi Jungmin, Hong Juhyeon, Hunt David, de Burca Anna, Kim Soo Yeon, Kim Taekeun, Lee Seungbok, Redman Melody, Rius Rocio, Simons Cas, Tan Tiong Yang, Ellingford Jamie, O'Keefe Raymond T, Chae Jong Hee, Banka Siddharth
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Nat Genet. 2025 Jun;57(6):1362-1366. doi: 10.1038/s41588-025-02209-y. Epub 2025 May 29.
R-loops are DNA-RNA hybrid structures that may promote mutagenesis. However, their contribution to human Mendelian disorders is unexplored. Here we show excess de novo variants in genomic regions that form R-loops (henceforth, 'R-loop regions') and demonstrate enrichment of R-loop region variants (RRVs) in ribozyme, snoRNA and snRNA genes, specifically in rare disease cohorts. Using this insight, we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, RNU2-2 and RNU5B-1. These, along with the recently described RNU4-2-related ReNU syndrome, provide a genetic explanation for a substantial proportion of individuals with NDDs.
R环是一种可能促进诱变的DNA-RNA杂交结构。然而，它们对人类孟德尔疾病的影响尚未得到探索。在这里，我们展示了在形成R环的基因组区域（以下简称“R环区域”）中存在过量的新生变异，并证明了R环区域变异（RRV）在核酶、snoRNA和snRNA基因中富集，特别是在罕见病队列中。基于这一发现，我们报告了由两个主要剪接体RNA编码基因RNU2-2和RNU5B-1中的罕见变异引起的神经发育障碍（NDD）。这些变异，连同最近描述的与RNU4-2相关的ReNU综合征，为相当一部分NDD患者提供了遗传学解释。
