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. 2026 Feb 23.
doi: 10.1111/cge.70154. Online ahead of print.

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

Juhyeon Hong  1 , Seungbok Lee  2   3 , Soo Yeon Kim  2   3 , Taekeun Kim  1 , Woong-Hee Shin  4 , Sesong Jang  3 , Ji-Hwan Park  5 , Dongmin Jang  6 , Gunwoo Park  7 , Jong Ho Cha  3 , Jae So Cho  8 , Anna Cho  8 , Hunmin Kim  8 , Hyewon Woo  9 , Jon Soo Kim  9 , Byung Chan Lim  3 , Ji Eun Lee  10 , Myungshin Kim  11 , Chong Kun Cheon  12 , Jungmin Choi  1 , Jong-Hee Chae  2   3
Affiliations

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

Juhyeon Hong et al. Clin Genet. .

Abstract

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.

Keywords: RNU4‐2; U4 snRNA; neurodevelopmental disorders; whole‐genome sequencing.

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