RNU5B-1-Related Neurodevelopmental Disorder with Seizures and Joint Laxity (NEDSJL): Research Report

Scope and reliability. This is a very recent, rare, non-coding-gene disorder. I read two primary papers directly. I could not open the OMIM pages (HTTP 403), so OMIM details come only from search-result summaries and are marked "unverified". Most template sections (environment, protective factors, treatment, models and so on) have no disease-specific literature, and I say so. I did not run the prescribed ontology-term lookups. Every HPO, GO, CL, UBERON and NCIT ID below is a suggested name only, not a validated CURIE. Look each one up before binding it.

Important discrepancy. The disease name, from OMIM, includes "joint laxity". The two primary papers I could read do not clearly report joint hypermobility in RNU5B-1 carriers. In Nava et al., hypermobility appears only in the RNU4-2 cohort. Jackson et al. do not mention it in the text I could access. The OMIM clinical synopsis may draw on the supplementary tables or on unpublished data, and I could not check it. A curator should check the OMIM entry text and the supplements before asserting hypermobility or "seizures" as high-frequency features.

1. Disease Information

• Overview. NEDSJL is an autosomal dominant neurodevelopmental disorder. It is caused by de novo heterozygous variants in RNU5B-1, which encodes one of the paralogs of U5 small nuclear RNA, a core component of the major spliceosome. The variants cluster in the highly conserved loop I of U5 (about n.30–n.50). The main features are global developmental delay or intellectual disability, hypotonia, macrocephaly or other head-size abnormality, failure to thrive, and brain MRI abnormalities.
• Identifiers.
• OMIM phenotype #621302 (NEDSJL) and OMIM gene *621090 (RNU5B-1). These come from search-result titles and are unverified in full. See OMIM 621302 and OMIM 621090.
• MONDO:1060179 was supplied in the request. I did not independently confirm it.
• Orphanet, ICD and MeSH: not found.
• Synonyms. Neurodevelopmental disorder with seizures and joint laxity; NEDSJL; RNU5B-1-related neurodevelopmental disorder.
• Source of data. The data are individual-level, from clinical sequencing cohorts. These are the UK 100,000 Genomes Project (100KGP), a French rare-disease cohort and international collaborators. There is no aggregate registry.

2. Etiology

• Cause. Heterozygous, mostly de novo, variants in RNU5B-1 on 15q22 (n. positions on ENST00000363286.1). The constrained region is n.30–n.50.
• Origin of the variants. In Nava et al., phased loop I variants arose mostly on the maternal allele. Five of seven phaseable loop I variants were maternal: n.39C>G, n.42_43insA and three n.44A>G (PMC12165858). Jackson et al. likewise report that n.39_40insT "is highly likely to have arisen on the maternal allele" (PMC12165836).
• Risk and protective factors. None identified. Searches turned up no data on environmental, protective or gene–environment factors. Jackson et al. found RNU5B-1 by looking for R-loop-forming regions with de novo variants, which concerns where mutations arise, not an environmental risk factor.

3. Phenotypes

Clinical data are sparse, and the figures below mix two papers with overlapping individuals.

• Onset and course. Developmental from infancy. Progression, quality of life and age-specific frequencies are not reported.
• Possible allele-specific head-size effects. Nava propose that variant-specific effects could explain opposing head-growth phenotypes (macrocephaly with n.39C>G, acquired microcephaly with n.44A>G). They state larger studies are needed to confirm this.
• OMIM numbers I could not verify. One search summary said OMIM lists epilepsy in 4, motor delay in 4, joint hypermobility in 4 and autism in 3. That conflicts with the one-in-nine epilepsy figure from Nava, possibly because the cohorts differ. Treat it as unverified.

4. Genetic/Molecular Information

• Gene. RNU5B-1 (HGNC symbol RNU5B-1; look up the HGNC ID, which I did not retrieve). It is one of five U5 snRNA paralogs. RNU5A-1 is a related candidate gene.
• Variants (n. numbering on ENST00000363286.1):
• Recurrent loop I variants: n.39C>G, n.42_43insA, n.44A>G. Nava classify all three as likely pathogenic.
• Single or rare variants: n.37G>C, n.39_40insT, and others outside loop I (n.24G>C, n.74T>C; paternal in Nava, unclear significance).
• Variants of doubtful relevance: n.100C>G (the carrier had an alternative diagnosis), n.59G>C (also in three unaffected 100KGP participants), n.39C>T (three gnomADv4 individuals).
• Jackson reports nine individuals with rare variants in the constrained region. Nava report 18 NDD probands with de novo RNU5B-1 variants, 17 of them in the critical region. Together with RNU5A-1, that makes 21 individuals.
• Jackson's table lists n.39_40insT and n.37G>C and does not list n.39C>G, while Nava's lists n.39C>G; the two papers may use different numbering or overlapping patients. I did not reconcile them.
• Mechanism class. Non-coding RNA variants of a likely dominant-negative or altered-function type. This is inferred, not shown directly.
• Variant frequency. The constrained region is depleted of variants in gnomADv4.
• Origin. Germline, de novo.
• Epigenetic and chromosomal features. None reported.

5. Environmental Information

No environmental, lifestyle or infectious factors are reported.

6. Mechanism / Pathophysiology

Causal chain (steps 3 to 6 are inferred rather than demonstrated for RNU5B-1):

1. A de novo heterozygous variant arises, often on the maternal allele, in the loop I region of RNU5B-1. The region was identified through R-loop-forming-region analysis (Jackson).
2. The variant changes the sequence of U5 snRNA loop I. The sequence is invariantly conserved and binds and aligns exons during splicing.
3. In the spliceosome, altered loop I disrupts exon alignment. Nava note that "U5 loop I is crucial for 5′SS transfer."
4. This leads to variant-specific splicing changes, which Nava found in patient transcriptomes. n.39C>G mainly affected 5′ splice sites, n.44A>G mainly affected 3′ splice sites, and RNU5A-1 variants showed other patterns. The RNU5 variants lacked the shared signature seen with RNU4-2.
5. Mis-splicing of many transcripts is thought to impair brain development. The specific genes involved are unknown.

6. The outcome is the neurodevelopmental phenotype (delay, hypotonia, head-size change, MRI abnormalities, seizures in a minority).

7. Expression. Jackson report high RNU5B-1 expression in developing brain and retina (ENCODE small RNA-seq). This is consistent with the neural phenotype.

8. Functional evidence level. Jackson report no direct functional assays of RNU5B-1. Nava provide limited transcriptomic data from small patient numbers.
9. Suggested GO terms (look up): spliceosomal complex; U5 snRNP; mRNA splicing via spliceosome; mRNA 5′-splice site recognition. Suggested CL: neurons and neural progenitors (inferred). Suggested subcellular location: nucleus, spliceosome.

7. Anatomical Structures Affected

Brain and nervous system (all nine patients had MRI abnormalities; corpus callosum hypoplasia was reported for one individual in Jackson's figure, but the gene cohort is not stated). Other involved sites are eye, chest wall (pectus excavatum), heart, lung, teeth and the sacrococcygeal region (small counts). Laterality is not reported.

8. Temporal Development

Onset is early, during development. Natural history, progression and critical windows have not been described.

9. Inheritance and Population

• Autosomal dominant, de novo. Parental origin is skewed to maternal in phaseable cases. Germline mosaicism and recurrence in siblings were not described.
• Penetrance and expressivity: apparently high penetrance among ascertained cases, with variable severity. Not formally estimated.
• Prevalence, incidence, sex ratio and geographic distribution: not available. Cases come from the UK, France and international collaborators, with a few dozen total.
• Recurrent variants (n.44A>G, n.42_43insA, n.39C>G) are mutational hotspots, not founder alleles.

10. Diagnostics

• Genetic testing. Exome sequencing generally does not cover snRNA genes, and some mapping filters flag them. Genome sequencing, or targeted analysis of snRNA genes, is needed. Jackson note that the n.42_43insA variant failed a stringent "altreadparent" filter in two cases, but manual IGV review showed no good-quality alternate reads in the parents. This indicates that pipeline filters can hide real de novo calls.
• Imaging. Brain MRI abnormalities are common; the specific findings are not described in the text I accessed.
• Differential diagnosis. RNU4-2 (ReNU) syndrome, RNU2-2 developmental and epileptic encephalopathy, and other spliceosomopathies. Nava found that RNU5 and RNU4-2 patients differ in splicing signature and clinical profile.
• No biomarkers or clinical criteria exist. No screening programme exists.

11. Outcome / Prognosis

Not reported. Most reported patients have severe developmental delay, but survival and long-term outcomes are unknown.

12. Treatment

No disease-specific therapy was found. Care is supportive: developmental therapies (NCIT rehabilitation, physical therapy, speech-language therapy), antiseizure medication for the minority with epilepsy, and nutritional support for failure to thrive. This is general practice, not drawn from RNU5B-1 literature. No clinical trials were identified. Antisense approaches to snRNA disorders are conceptual only.

13. Prevention

Genetic counselling is warranted. The recurrence risk appears low because the variants are de novo, but germline mosaicism cannot be excluded. No prevention strategies are known.

14. Other Species / Natural Disease

Not applicable. U5 snRNA is highly conserved, but no animal disease equivalents were found.

15. Model Organisms

No RNU5B-1 models were found. The U5 paralogs are redundant genes, which complicates modelling, and a patient-derived or edited cell line would be the likely route. This is my inference, not published work.

Key Citations

• Nava C, et al. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. Nat Genet 2025;57(6):1374–1388. PMID 40379786; DOI 10.1038/s41588-025-02184-4. PMC12165858. Also available as a medRxiv preprint.
• Jackson R, et al. Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes. Nat Genet 2025;57(6):1362–1366. PMID 40442284; DOI 10.1038/s41588-025-02209-y. PMC12165836.
• OMIM #621302 and *621090 (not directly read).
• GeneCards RNU5B-1 and MalaCards NEDSJL (secondary sources).

Curation Recommendations

• Resolve the joint-laxity and seizure discrepancy against the OMIM entry text and supplementary tables before encoding frequencies.
• Do not state any splicing mechanism for RNU5B-1 as established. Nava's data come from small numbers of patients.
• Run just fetch-reference PMID:40379786 and PMID:40442284, then quote exact snippets from the cached text. The quotes above were relayed by a summarizing tool, so verify them against the cache.
• Look up every ontology ID and the HGNC ID in the same step you write it.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

• PMC:PMC12165836: "is highly likely to have arisen on the maternal allele"
• closest text in source: "Variants that pass base filter are then subject to the stringent filter, which include the following: altreadparent_filter (no more than one read supporting the alternate allele in either the mother or the father); abratio_filter (the AB ratio in the offspring is between 0.3 and 0.7); proximity_filter (DNV is not located within 20 bp of another DNV within the same trio); segmentalduplication_filter (no overlap with segmental duplications); simplerepeat_filter (no overlap with simple repeat regions; patch_filter (no overlap with patch regions); stringent_filter (**all base and stringent filters pass)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Every term resolved, and every label the report gave matched.