Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes
Adam Jackson, Nishi Thaker, Alexander J. M. Blakes, Gillian Rice, Sam Griffiths‐Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo‐Yeon Kim, T. Kim, Seungbok Lee, Melody Redman, Rocío Rius, Cas Simons, Tiong Yang Tan, Jamie M. Ellingford, Raymond T. O’Keefe, Jong‐Hee Chae, Siddharth Banka
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.