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

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

doi:10.1038/s41588-025-02209-y

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

Jackson, Adam;
Thaker, Nishi;
Blakes, Alexander;
Rice, Gillian;
Griffiths-Jones, Sam;
... Choi, Jungmin;
외 17명

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초록

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.

키워드

Ribonucleoprotein, U5 Small Nuclear; Rna, Small Nuclear; Rna, Small Nucleolar; Ribozyme; Small Nuclear Rna; Small Nucleolar Rna; Small Nuclear Ribonucleoprotein; Adolescent; Article; Child; Cohort Analysis; Controlled Study; Dna Rna Hybridization; Gene; Gene Identification; Genetic Variability; Genomics; Human; Human Tissue; Major Clinical Study; Mental Disease; Monogenic Disorder; Mutagenesis; Preschool Child; Rare Disease; Rnu2 2 Gene; Rnu5b 1 Gene; School Child; Spliceosome; Conformation; Genetics; Mutation; Humans; Mutation; Neurodevelopmental Disorders; Nucleic Acid Conformation; Ribonucleoprotein, U5 Small Nuclear; Rna, Small Nuclear; Rna, Small Nucleolar; SNRNA; MUTATION

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

저자: 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

DOI: 10.1038/s41588-025-02209-y

발행일: 2025-05-29

유형: Article; Early Access

저널명: Nature Genetics

권: 57

호: 6

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