Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-05-29 DOI:10.1038/s41588-025-02209-y

Adam Jackson, Nishi Thaker, Alexander Blakes, Gillian Rice, Sam Griffiths-Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo Yeon Kim, Taekeun Kim, Seungbok Lee, Melody Redman, Rocio Rius, Cas Simons, Tiong Yang Tan, Jamie Ellingford, Raymond T. O’Keefe, Jong Hee Chae, Siddharth Banka

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Abstract

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. Genomic analyses focused on regions that form R-loops identify rare mutations in RNU2-2 and RNU5B-1 in individuals with neurodevelopmental disorders.

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R-loop形成区分析确定RNU2-2和RNU5B-1为神经发育障碍基因

r -环是DNA-RNA杂交结构，可能促进突变。然而，它们对人类孟德尔障碍的贡献尚未被探索。在这里，我们展示了在形成r环的基因组区域（以下称为“r环区域”）中过量的新生变异，并证明了核酶、snoRNA和snRNA基因中r环区域变异（RRVs）的富集，特别是在罕见疾病队列中。利用这一见解，我们报道了由两个主要剪接体RNA编码基因RNU2-2和RNU5B-1的罕见变异引起的神经发育障碍（ndd）。这些，连同最近描述的rnu4 -2相关的ReNU综合征，为相当大比例的ndd患者提供了遗传学解释。

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution