Childhood onset hereditary spastic paraplegia

Gene: RNU4-2

Green List (high evidence)

Comment on list classification: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder, of which spasticity was reported in over 10 families. Spasticity was not reported as one of the presentations of ReNU syndrome (MIM #620851) that is associated with monoallelic RNU4-2 variants. Hence, the MOI should be set as 'BIALLELIC, autosomal or pseudoautosomal' and the gene should be promoted to green rating in the next GMS update.

Created: 20 Apr 2026, 5:08 p.m. | Last Modified: 20 Apr 2026, 5:08 p.m.

Panel Version: 8.51

PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Spasticity was reported in 14 individuals from 11 families, while movement and coordination abnormalities were observed in 13 of 31 individuals, nine with ataxia, three with dystonia, one with choreoathetosis and one unspecified abnormality of coordination.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature

Created: 20 Apr 2026, 5:04 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 41951737
• 41951959