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

Area of Science:

• Genetics
• Molecular Biology
• Human Disease

Background:

• R-loops are DNA-RNA hybrid structures implicated in mutagenesis.
• The role of R-loops in human Mendelian disorders remains largely unexplored.
• Identifying genetic underpinnings of rare diseases is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the contribution of R-loops to human Mendelian disorders.
• To identify specific genes and genomic regions associated with R-loop formation and disease.
• To uncover novel genetic causes for neurodevelopmental disorders (NDDs).

Main Methods:

• Analysis of de novo variants in genomic regions prone to R-loop formation.
• Enrichment analysis of R-loop region variants (RRVs) in specific gene types (ribozyme, snoRNA, snRNA) within rare disease cohorts.
• Genetic analysis of spliceosomal RNA encoding genes in patients with NDDs.

Main Results:

• An excess of de novo variants was observed in R-loop forming regions.
• RRVs were significantly enriched in ribozyme, snoRNA, and snRNA genes in rare disease cohorts.
• Rare variants in RNU2-2 and RNU5B-1, major spliceosomal RNA genes, were identified as a cause of NDDs.

Conclusions:

• R-loop regions are a source of potentially pathogenic variants in human genetic disorders.
• Variants in spliceosomal RNA genes like RNU2-2 and RNU5B-1 contribute to NDDs.
• This study provides a genetic explanation for a significant subset of individuals with NDDs and highlights R-loops as a disease-associated structure.