Early onset or syndromic epilepsy

Gene: RNU4-2

Green List (high evidence)

MedRxiv preprint Jonghe et al., 2025 doi: https://doi.org/10.1101/2025.04.08.25325442

Recessive NDD associated with variants in RNU4-2:

Jonghe et al. identified sixteen individuals from global rare disease cohorts with biallelic RNU4-2 variants: nine (including three pairs of siblings) with homozygous variants and seven (including three pairs of siblings) who were each concordant for compound heterozygous variants. None of these variants were located in the ReNU syndrome critical region, yet all sixteen individuals had NDD phenotypes. The sixteen identified individuals had a novel neurodevelopmental disorder characterised by global developmental delay, intellectual disability, delayed or absent speech, hypotonia, spasticity, microcephaly, ophthalmological and visual impairments, and seizures, with variable involvement of genitalia, skin, hair, and limb anomalies. On MRI, individuals show distinctive white matter abnormalities and cerebellar atrophy that are not seen in ReNU syndrome. The clinical phenotypes of these individuals will be discussed further in a companion manuscript.

Created: 23 Apr 2025, 2:19 p.m. | Last Modified: 23 Apr 2025, 2:19 p.m.

Panel Version: 7.90

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).

Created: 12 Mar 2025, 1:50 p.m. | Last Modified: 12 Mar 2025, 1:50 p.m.

Panel Version: 7.54

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 10:58 a.m. | Last Modified: 26 Sep 2024, 10:58 a.m.

Panel Version: 6.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: Multiple individuals have been identified in PMID: 38821540 with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2. Additional cases with mutual findings have also been reported in PMID: 38645094, corroborating this gene-disease association - however, PMID: 38645094 is still in preprint at this time.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.

Created: 7 Jun 2024, 2 p.m. | Last Modified: 4 Jul 2024, 9:06 a.m.

Panel Version: 5.20

Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID: 38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.

Created: 7 Jun 2024, 1:44 p.m. | Last Modified: 4 Jul 2024, 9:09 a.m.

Panel Version: 5.20

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

Publications

• 38821540
• 38645094

PubMed ID: 38645094 is still a pre-print. We will wait until the paper is peer reviewed and published before adding to panels. This gene should also be added to the Epilepsy panel.

Created: 23 May 2024, 8:59 p.m. | Last Modified: 23 May 2024, 8:59 p.m.

Panel Version: 6.13

Green List (high evidence)

Over 100 individuals reported with NND and heterozygous variants in a 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III). The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). Variants in this region likely explain 0.41% of individuals with NDD.
Sources: Literature

Created: 23 Apr 2024, 8:39 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related

Publications

• 38645094