Early onset or syndromic epilepsy

Gene: RNU2-2P

Green List (high evidence)

Comment on mode of inheritance: There are numerous individuals reported with both mono- and bi-allelic variants causing a neurodevelopmental disorder including early-onset epilepsy. Hence MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.

Created: 10 Apr 2026, 2:21 p.m. | Last Modified: 10 Apr 2026, 2:21 p.m.

Panel Version: 8.177

PMID: 41912933 Jackson et al., 2026 - online ahead of print
Study identified 122 individuals from 100kGP with biallelic RNU2-2 variants. 27 unrelated families are described in more detail. Most common phenotypes: ‘generalized seizures’, ‘encephalopathy’, ‘intellectual disability’ and ‘delayed speech and language development'. Motor delay and seizures affected 94% of patients, 21/34 patients had seizure onset in the first year of life. Brain MRI was abnormal in 46% of 28 patients assessed, 9/28 individuals had cerebral atrophy.

Created: 10 Apr 2026, 2:18 p.m. | Last Modified: 10 Apr 2026, 2:18 p.m.

Panel Version: 8.176

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 119, OMIM:621304

Publications

• 41912933

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Mar 2026, 3:39 p.m. | Last Modified: 11 Mar 2026, 3:39 p.m.

Panel Version: 8.134

Comment on list classification: There is sufficient evidence available for the association of this gene with epilepsy. Hence, this gene can be promoted to green rating on the next GMS update.

Created: 14 Apr 2025, 10:38 a.m. | Last Modified: 14 Apr 2025, 10:38 a.m.

Panel Version: 7.90

The "new-gene-name" tag has been added as the official HGNC symbol for RNU2-2P is RNU2-2.

In addition, "locus-type-rna-small-nuclear" tag has been added to highlight the biotype for this gene.

Created: 14 Apr 2025, 10:36 a.m. | Last Modified: 14 Apr 2025, 10:36 a.m.

Panel Version: 7.89

PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behaviour, microcephaly, hypotonia, epilepsy and hyperventilation. The phenotype typically manifests from 3 to 6 months of age but is progressive, frequently severe and accompanied by characteristic dysmorphic features. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

Created: 14 Apr 2025, 10:33 a.m. | Last Modified: 14 Apr 2025, 10:33 a.m.

Panel Version: 7.86

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027

Publications

• 40210679

Red List (low evidence)

PRE-PRINT article https://doi.org/10.1101/2024.09.03.24312863

Greene et al 2024 - report 15 cases in which recurrent germline variants in RNU2-2P are found in patients with a severe neurodevelopmental disorder.

9 cases were from the 100,000 Genomes Project, all of which were annotated with Intellectual disability and displayed severe epilepsy usually from the first few months of life. Among these 9 two recurrent variants were found; n.4G>A and n.35A>G. Trio sequencing of 4/5 of the cases with n.4G>A and 3/4 of the cases with n.35A>G showed that the variants were de novo in all cases.

A variant with a different alternate allele at nucleotide 35, n.35A>T, was identified in
8 unaffected participants but further analysis suggests that this is a recurring somatic mosaic
variant.

A further 6 cases were identified in additional datasets of patients with neurodevelopmental abnormalities with de novo variants and no unaffected carriers of either variant; 4 cases had n.4G>A, 1 case had n.35A>G and 1 case had a different alternate allele, n.35A>C.

RNU2-2P is currently annotated as a pseudogene in Ensembl, but there is evidence that it is a transcribed gene from PMID.: 35288589
Sources: Literature

Created: 10 Sep 2024, 9:34 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown