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

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

doi:10.1038/s41588-025-02209-y

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

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 EllingfordRaymond T O'Keefe, Jong Hee Chae, Siddharth Banka

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1362–1366
Number of pages	19
Journal	Nature Genetics
Volume	57
Issue number	6
Early online date	29 May 2025
DOIs	https://doi.org/10.1038/s41588-025-02209-y
Publication status	Published - 1 Jun 2025

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Jackson, A., Thaker, N., Blakes, A., Rice, G., Griffiths-Jones, S., Balasubramanian, M., Campbell, J., Shannon, N., Choi, J., Hong, J., Hunt, D., de Burca, A., Kim, S. Y., Kim, T., Lee, S., Redman, M., Rius, R., Simons, C., Tan, T. Y., ... Banka, S. (2025). Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes. Nature Genetics, 57(6), 1362–1366. https://doi.org/10.1038/s41588-025-02209-y

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

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.",

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Jackson, A, Thaker, N, Blakes, A, Rice, G , Griffiths-Jones, S, Balasubramanian, M, Campbell, J, Shannon, N, Choi, J, Hong, J, Hunt, D, de Burca, A, Kim, SY, Kim, T, Lee, S, Redman, M, Rius, R, Simons, C, Tan, TY, Ellingford, J , O'Keefe, RT, Chae, JH & Banka, S 2025, 'Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes', Nature Genetics, vol. 57, no. 6, pp. 1362–1366. https://doi.org/10.1038/s41588-025-02209-y

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AU - Jackson, Adam

AU - Thaker, Nishi

AU - Blakes, Alexander

AU - Rice, Gillian

AU - Griffiths-Jones, Sam

AU - Balasubramanian, Meena

AU - Campbell, Jennifer

AU - Shannon, Nora

AU - Choi, Jungmin

AU - Hong, Juhyeon

AU - Hunt, David

AU - de Burca, Anna

AU - Kim, Soo Yeon

AU - Kim, Taekeun

AU - Lee, Seungbok

AU - Redman, Melody

AU - Rius, Rocio

AU - Simons, Cas

AU - Tan, Tiong Yang

AU - Ellingford, Jamie

AU - O'Keefe, Raymond T

AU - Chae, Jong Hee

AU - Banka, Siddharth

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

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