Exploring the Impact of RNU4-2 Defects on Neurodevelopmental Disorders in a Korean Population

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Neurodevelopmental disorders (NDDs) often have unexplained genetic origins.
• Non-coding genomic elements are frequently under-assessed in NDD diagnostics.
• Recent research suggests spliceosomal RNA genes may play a role in NDDs.

Purpose of the Study:

• To investigate the role of the RNU4-2 gene in unexplained neurodevelopmental disorders.
• To identify pathogenic variants in RNU4-2 and characterize their functional impact.
• To establish RNU4-2 variants as a cause of early-onset NDDs.

Main Methods:

• Whole-genome sequencing of 15,450 Korean individuals, including 2,797 NDD probands.
• RNA secondary structure modeling and molecular dynamics simulations.
• Whole-blood RNA sequencing (RNA-seq) in variant carriers.

Main Results:

• Rare pathogenic RNU4-2 variants were found in 0.72% of NDD probands, with a recurrent n.64_65insT variant in 85% of these cases.
• The n.64_65insT variant disrupts U4/U6 snRNA duplex formation and impairs splice site recognition.
• Variant carriers exhibited altered gene expression in immune, chromosomal, and DNA metabolic pathways, alongside NDD phenotypes.

Conclusions:

• RNU4-2, particularly the n.64_65insT variant, is a significant cause of early-onset neurodevelopmental disorders.
• Routine assessment of spliceosomal RNA genes is recommended for genomic diagnostics.
• Reanalysis of unsolved NDD cases may improve diagnostic yield and genetic counseling.