韓国人集団におけるRNU4-2欠損が神経発達障害に及ぼす影響の検討

Neurodevelopmental disorders (NDDs) often remain unexplained due to limited assessment of non-coding genomic elements. Motivated by recent reports implicating RNU4-2, which encodes a spliceosomal small nuclear RNA (snRNA), we analyzed whole-genome sequencing data from 15 450 Korean individuals, including 2797 unrelated NDD probands. Rare pathogenic RNU4-2 variants were identified in 20 probands (0.72%), including 17 (85%) with a recurrent n.64_65insT variant. RNA secondary structure modeling and molecular dynamics simulations demonstrated that n.64_65insT disrupts the U4/U6 snRNA duplex and impairs exposure of the U6 ACAGAGA motif required for 5' splice-site recognition. Whole-blood RNA-seq from carriers revealed increased alternative 5' splice-site usage and dysregulation of immune, chromosomal, and DNA metabolic gene programs. Clinically, affected individuals presented with global developmental delay, microcephaly, seizures, failure to thrive, and dysmorphic features. These findings establish RNU4-2, particularly n.64_65insT, as a cause of early-onset NDD. We advocate for routine assessment of spliceosomal RNA genes in genomic diagnostics and reanalysis of unsolved cases to improve yield and guide counseling in rare neurodevelopmental syndromes.