This month’s highlighted publication in Nature Genetics, led by Professor Siddharth Banka and Dr Adam Jackson from The University of Manchester, identifies novel de novo variants in two small nuclear RNA (snRNA) genes—RNU2-2 and RNU5B-1—as causes of neurodevelopmental disorders (NDDs). Analyzing over 975,000 de novo variants from the 100,000 Genomes Project, the study revealed a significant enrichment of mutations within genomic regions prone to forming R-loops—DNA–RNA hybrids associated with genomic instability.
The researchers demonstrated that variants in RNU2-2 and RNU5B-1, both integral to the spliceosomal complex involved in RNA splicing, lead to distinct clinical phenotypes. Mutations in RNU2-2 were associated with global developmental delay, speech impairment, epilepsy, and clinical features similar to Rett and Pitt–Hopkins syndromes. Conversely, RNU5B-1 variants correlated with developmental delay, hypotonia, macrocephaly, and failure to thrive.
This study extends the range of spliceosomal snRNA genes known to cause human diseases, following recent discoveries of related syndromes. The findings underscore the importance of noncoding RNA genes and advocate integrating R-loop mapping into genomic diagnostics, improving detection rates for genetic variants associated with previously undiagnosed neurodevelopmental disorders.
Reference:
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. Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes. Nat Genet. 2025 May 29. doi: 10.1038/s41588-025-02209-y. . PMID: 40442284.
