Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes
Variant / mechanism
RNU4-2 (biallelic — homozygous or compound heterozygous, variants outside the ReNU region)
Biallelic variants in a U4 spliceosomal snRNA, clustered in Stem II, k-turn and Sm site — loss of function via reduced transcript levels
Summary
Description of a novel recessive neurodevelopmental disorder, distinct from the ReNU syndrome (dominant de novo), in 38 individuals carrying biallelic variants in RNU4-2. Variants cluster within key functional elements of U4 RNA (Stem II, k-turn, Sm site). Characteristic imaging with white matter abnormalities and enlarged perivascular spaces. LOF mechanism distinct from ReNU, confirmed by reduced transcript levels.
Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.
Analysis
Diagnostic alert: in an NDD patient with distinctive white matter changes (enlarged perivascular spaces) and no variant in the canonical ReNU region, interrogate the rest of RNU4-2 for biallelic status. Third 2026 paper highlighting the importance of spliceosomal snRNAs in constitutional genetics — to integrate into ES/GS pipelines.
Why this score?
new syndrome +3; biallelic +2; functional (transcript levels) +2; 38 individuals +1; distinctive imaging +1; Nature Genetics +1