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Intellectual disability

Gene: RNU4-2

Green List (high evidence)
RNU4-2 (RNA, U4 small nuclear 2)
EnsemblGeneIds (GRCh38): ENSG00000202538
EnsemblGeneIds (GRCh37): ENSG00000202538
RNU4-2 is in 6 panels

5 reviews

Hayley Lees (NHS)

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, 2:18 p.m. | Last Modified: 23 Apr 2025, 2:18 p.m.
Panel Version: 8.242

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Created: 23 Apr 2025, 2:18 p.m.
Last Modified: 23 Apr 2025, 2:18 p.m.
Panel version: 8.242

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Created: 12 Mar 2025, 1:51 p.m. | Last Modified: 12 Mar 2025, 1:51 p.m.
Panel Version: 8.129
The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Created: 26 Sep 2024, 2:57 p.m. | Last Modified: 26 Sep 2024, 2:57 p.m.
Panel Version: 7.41

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 26 Sep 2024, 2:57 p.m.
Last Modified: 26 Sep 2024, 2:57 p.m.
Panel version: 7.41

Arina Puzriakova (Genomics England Curator)

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: 6.50
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: 6.50

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

Publications

Created: 7 Jun 2024, 1:44 p.m.
Last Modified: 4 Jul 2024, 9:09 a.m.
Panel version: 6.16

Eleanor Williams (Genomics England Curator)

Additional paper PMID:38991538 Chen et al 2024 supporting the association of RNU4-2 variants with a neurodevelopmental disorder. Data from the 100,000 Genomes Project dataset (used in other studies).
Created: 17 Nov 2024, 10:16 p.m. | Last Modified: 17 Nov 2024, 10:16 p.m.
Panel Version: 8.34
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

Publications

Created: 23 May 2024, 8:59 p.m.
Last Modified: 23 May 2024, 8:59 p.m.
Panel version: 8.34

Zornitza Stark (Australian Genomics)

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

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

Panel version: 5.536

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • ReNU syndrome, OMIM:620851
Tags
locus-type-rna-small-nuclear gene-checked
Clinvar variants
Variants in RNU4-2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

12 Mar 2025, Gel status: 3

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851

17 Nov 2024, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: RNU4-2 were set to 38821540; 38645094

2 Oct 2024, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag gene-checked tag was added to gene: RNU4-2.

26 Sep 2024, Gel status: 3

Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q2_24_promote_green was removed from gene: RNU4-2.

26 Sep 2024, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source NHS GMS was added to RNU4-2. Source Expert Review Green was added to RNU4-2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

7 Jun 2024, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).

7 Jun 2024, Gel status: 0

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2. Tag Q2_24_promote_green tag was added to gene: RNU4-2.

7 Jun 2024, Gel status: 0

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: RNU4-2 were set to 38645094

23 Apr 2024, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: RNU4-2 was added gene: RNU4-2 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RNU4-2 were set to 38645094 Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related Review for gene: RNU4-2 was set to GREEN