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<p>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, <i>RNU2-2</i> and <i>RNU5B-1</i>. These, along with the recently described <i>RNU4-2</i>-related ReNU syndrome, provide a genetic explanation for a substantial proportion of individuals with NDDs.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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  • 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

摘要

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.