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

Pathogenic RNU4-2 variants (recurrent n.64_65insT), U4 spliceosomal RNA, disruption of U4/U6 duplex

Whole genome sequencing analysis of 15,450 Korean individuals including 2,797 undiagnosed NDD probands identifies pathogenic RNU4-2 variants in 20 probands (0.72%). The recurrent n.64_65insT variant is present in 85% of them. RNU4-2 encodes the U4 spliceosomal RNA involved in 5' donor site recognition. RNA secondary structure modeling demonstrates that n.64_65insT disrupts the U4/U6 duplex, with molecular dynamics simulation confirming functional effect. This Korean population replication consolidates RNU4-2 as a major NDD gene to include in diagnostic WGS.

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RNU4-2 is an emblematic example of a non-coding gene of major clinical relevance, long invisible by exome and panel sequencing. Its 0.72% prevalence among undiagnosed NDD probands in a Korean cohort — consistent with European data — confirms cross-population significance and makes a compelling case for systematic WGS in pediatric NDD.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 0/1 → Total: 7/10