👪

Inheritance

1

Autosomal dominant, de novo HP:0000006

Heterozygous variants, almost always de novo. Of seven phased loop I variants, five arose on the maternal allele and two on the paternal allele.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:40379786 SUPPORT Human clinical

"six NDD probands had five de novo variants in RNU5B-1, compared to a single de novo variant in a non-NDD individual"

De novo heterozygous RNU5B-1 variants are enriched in neurodevelopmental disorder probands relative to other rare-disease participants.

PMID:40379786 SUPPORT Human clinical

"Among the phaseable RNU5B-1 variants located in the U5 5′ loop I, five (n.39C>G, n.42_43insA and three n.44A>G) were phased to the maternal allele, while two (n.39C>G and n.37G>C) were on the paternal allele."

Reports the parental origin of phased loop I variants (five maternal, two paternal).

◈

Mechanistic Hypotheses

2

Variant-specific mis-splicing of neurodevelopmental transcripts

rnu5b1_missplicing_drives_brain_phenotype EMERGING

Evidence balance 1 support

The phenotype is caused by altered splice-site usage in a set of transcripts needed for brain development, with the set differing by variant according to which exon-boundary sequences pair with the mutant loop I. The loop I pairing part is an inference from normal spliceosome biology (PMID:39809319), not a model the disease papers propose. No such transcript has been identified, and the splicing data come from cultured lymphocytes of four RNU5B-1 carriers.

Pathograph links

Variant-Specific Altered Splice Site Usage -> Abnormal Brain Development INDIRECT UNKNOWN INTERMEDIATES

Deep research

OpenScientist citations 11 citations 2026-10-19T00:23:21.930179

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"These results, although obtained from a limited number of patients, may underline the clinical variability observed for patients with RNU5 variants."

The authors propose that the variant-specific splicing effects explain the clinical variability, while stating the data are limited.

Loss of functional U5B snRNP or broad spliceosome poisoning

rnu5b1_snrna_qc_loss_or_poisoning ALTERNATIVE

Evidence balance 1 support

The phenotype follows from too little functional U5B snRNP, because the mutant snRNA is degraded by quality control, or from mutant U5B snRNP that assembles and impairs splicing broadly. Either predicts diffuse splicing disruption rather than a variant-specific target set. The evidence is from U4-2 mutants in cultured cells; a pure loss-of-function reading must also explain why heterozygous loss of one of several brain-expressed U5 genes would cause disease.

Pathograph links

RNU5B-1 Loop I Variant -> Reduced or Aberrant U5B snRNP Pool UNKNOWN

Reduced or Aberrant U5B snRNP Pool -> Abnormal Brain Development INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:42562572 SUPPORT INDIRECT In vitro / ex vivo

"Here, we identify multiple checkpoints in snRNA biogenesis monitored by quality control machineries that subject defective snRNAs to degradation and prevent their assembly into spliceosomes."

Establishes the degradation route that would lower the functional U5B pool if mutant U5B-1 is recognized as defective.

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Discussions and Knowledge Gaps

1

Which splicing errors caused by RNU5B-1 loop I variants produce the neurodevelopmental phenotype?

KNOWLEDGE GAP OPEN rnu5b1_which_splicing_errors_cause_phenotype

Attached to

pathophysiology#Variant-Specific Altered Splice Site Usage pathophysiology#Reduced or Aberrant U5B snRNP Pool pathophysiology#Abnormal Brain Development

The only patient splicing data come from cultured lymphocytes of four RNU5B-1 carriers. These showed no shared 5' or 3' splice-site signature, unlike ReNU syndrome, and the two recurrent variants appeared to act differently: n.39C>G mainly on 5' splice sites, n.44A>G mainly on 3' splice sites. No affected transcript has been tied to a neurodevelopmental gene, there are no neural RNA data, and the clinical picture may differ by variant (macrocephaly in two n.39C>G carriers, acquired microcephaly in three n.44A>G carriers). Whether the mutant U5 acts by dominant negative or altered-function effect has not been tested. A loop I model predicts that each variant re-weights splice sites whose upstream-exon sequence pairs with the mutant loop, which would make the target set variant-specific and could explain the clinical heterogeneity; that prediction is untested. A competing model holds that quality control degrades the mutant snRNA or that a stabilized mutant poisons spliceosomes broadly, which predicts diffuse rather than variant-specific disruption; measuring the level and spliceosome incorporation of mutant U5B-1 separates the two.

Proposed experiments

Splicing profiles of RNU5B-1 variants in human neural cells

rnu5b1_neuronal_splicing_by_variant

Introduce n.39C>G, n.42_43insA, n.44A>G and n.37G>C, each heterozygous, into an isogenic human iPSC line, differentiate to neural progenitors and cortical neurons, and profile splicing by deep RNA-seq with and without NMD inhibition. Compare each variant against the isogenic control and against each other, and test whether altered 5' splice sites are enriched for upstream-exon sequences predicted to pair differently with the mutant loop I. Because U5 is encoded by several genes, first confirm by allele-specific small RNA-seq that the mutant U5B-1 is expressed in neurons and incorporated into spliceosomes.

Would support

mechanistic_hypotheses#rnu5b1_missplicing_drives_brain_phenotype

Would refute

mechanistic_hypotheses#rnu5b1_missplicing_drives_brain_phenotype

Supporting outcome

Each variant produces a reproducible, variant-specific set of altered splice sites in neural cells, enriched for loop I pairing changes and for genes with established roles in brain development.

Refuting outcome

No reproducible splicing change beyond control variability in neural cells, or changes unrelated to loop I pairing, which would point to another mechanism such as altered snRNP biogenesis.

Show evidence (1 reference)

PMID:42856368 SUPPORT In vitro / ex vivo

"In a patient-derived induced pluripotent stem cell (iPSC) model of the recurrent RNU4-2 n.64_64insT variant, the splicing signature was fully recapitulated across all stages of differentiation into cortical neuron-like cells."

Shows the design is feasible in the sibling disorder: a blood splicing signature carried over to iPSC-derived cortical neurons. Preprint, and about RNU4-2, not RNU5B-1.

Level and spliceosome incorporation of mutant U5B-1

rnu5b1_mutant_u5_fate

In patient lymphoblastoid cells and in the isogenic iPSC-derived neurons above, measure mature U5B-1 by allele-specific small RNA-seq or primer extension, compare with RNU5A-1 and total U5, and test whether mutant U5B-1 is found in U5 snRNP, tri-snRNP and spliceosome fractions by affinity purification or glycerol-gradient fractionation followed by allele-specific sequencing. Repeat with quality-control factors such as the NEXT-exosome or TUT4/7 depleted to see whether mutant U5B-1 is being degraded.

Would support

mechanistic_hypotheses#rnu5b1_snrna_qc_loss_or_poisoning

Would refute

mechanistic_hypotheses#rnu5b1_snrna_qc_loss_or_poisoning

Supporting outcome

Mutant U5B-1 is depleted relative to the wild-type allele and recovers when quality control is inhibited, or it is incorporated but splicing changes are broad rather than variant-specific.

Refuting outcome

Mutant U5B-1 accumulates at wild-type levels and is incorporated into spliceosomes, which leaves altered splice-site selection by the mutant loop as the more likely mechanism.

Show evidence (1 reference)

PMID:42562572 SUPPORT In vitro / ex vivo

"These pathways also repress mutant snRNAs associated with human developmental disorders."

Motivates measuring mutant U5B-1 stability directly, since disease-mutant snRNAs can be degraded by these pathways.

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"These results, although obtained from a limited number of patients, may underline the clinical variability observed for patients with RNU5 variants."

The authors state that the splicing data are limited.

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Pathophysiology

5

RNU5B-1 Loop I Variant

A heterozygous de novo single-nucleotide substitution or small insertion in a roughly 8-nucleotide stretch (about n.37 to n.44) of RNU5B-1 that encodes the invariant 5' loop I of U5 snRNA. The stretch is depleted of variation in gnomAD and UK Biobank but not variant-free: a different substitution, n.39C>T, is present in three gnomADv4 individuals. Recurrent variants are n.39C>G, n.42_43insA and n.44A>G. RNU5B-1 and RNU5A-1 are the main U5 genes expressed in brain.

Loss of functional U5B snRNP or broad spliceosome poisoning

RNU5B-1 hgnc:10212

Downstream

Perturbed U5 Loop I Exon Alignment

Reduced or Aberrant U5B snRNP Pool

Show evidence (5 references)

PMID:40379786 SUPPORT Human clinical

"Seven of these variants (14 patients) clustered within a small region spanning chr15(hg38): 65,304,713–65,304,720, corresponding to the highly conserved U5 5′ loop I"

Localizes the pathogenic variants to U5 loop I.

PMID:40379786 SUPPORT Human clinical

"Three variants (n.39C>G, n.42_43insA and n.44AG) were recurrent, identified in six, three and four patients, respectively."

Names the recurrent variants.

PMID:40442284 SUPPORT Human clinical

"For RNU5B-1, we found three DN variants in a constrained region (from 30 to 50 bp; ENST00000363286.1:n.37G>C, n.42_43insA and n.44A>G) in four individuals"

Places de novo variants in the same constrained region. This 100,000 Genomes Project cohort overlaps the Genomics England arm of Nava et al.

+ 2 more references

Perturbed U5 Loop I Exon Alignment

U5 loop I base-pairs with the last nucleotides of the upstream exon, contributing to 5' splice-site selection, and holds both exons in register for exon ligation. A variant U5 snRNA incorporated into spliceosomes is expected to change which exon-boundary sequences pair well with loop I. Whether the mutant snRNA acts by dominant negative or altered-function effect, rather than by loss of function, has not been tested.

U5 loop I exon recognition and alignment during splicing GO:0000398 ⚠ ABNORMAL

U5 snRNP GO:0005682

Downstream

Variant-Specific Altered Splice Site Usage

Show evidence (2 references)

PMID:40379786 SUPPORT BACKGROUND Other

"U5 aligns exons by binding the 5′ and 3′ splice sites, ensuring precise ligation"

States the normal function of U5 that the variants perturb.

PMID:39809319 SUPPORT REVIEW SYNTHESIS Other

"Later, related approaches demonstrated that loop 1 of U5 snRNA base paired to exon sequence upstream of the 5′ splice site and that this was important for 5′ splice site selection"

Loop I pairing with the upstream exon contributes to 5' splice site choice, so changing loop I sequence would be expected to shift splice-site selection.

Variant-Specific Altered Splice Site Usage

In cultured lymphocytes from six individuals with U5 variants (four RNU5B-1), the variants did not reproduce the 5' splice-site signature of ReNU syndrome and shared no common 5' or 3' splice-site signature with each other. Analysed one at a time, RNU5B-1 n.39C>G possibly altered mainly 5' splice-site usage and n.44A>G mainly 3' splice-site usage; the authors call these possible variant-specific effects. The affected genes, and which events matter in brain, are not known.

Variant-specific mis-splicing of neurodevelopmental transcripts

mRNA 5'-splice site recognition GO:0000395 ⚠ ABNORMAL mRNA 3'-splice site recognition GO:0000389 ⚠ ABNORMAL

Downstream

Abnormal Brain Development

Show evidence (2 references)

PMID:40379786 SUPPORT Human clinical

"revealed possible variant-specific effects—RNU5B-1 n.39C>G mainly affected 5′SS, while RNU5B-1 n.44A>G primarily impacted 3′SS"

Patient RNA-seq showing which class of splice site each recurrent variant affects.

PMID:40379786 SUPPORT Human clinical

"These variants did not share the RNU4-2 5′SS signature (Extended Data Fig. 6e), and unlike RNU4-2 variants, RNU5 variants lacked a shared 5′SS or 3′SS signature."

Establishes that there is no common splicing signature across U5 variants.

Abnormal Brain Development

Structural brain abnormality is found on MRI in essentially every characterized patient, together with developmental delay. The mis-spliced transcripts that link the U5 defect to abnormal brain development have not been identified.

nervous system development GO:0007399 ⚠ ABNORMAL

Downstream

Global developmental delay

Seizures

Abnormal brain morphology

Generalized hypotonia

Macrocephaly

Acquired microcephaly

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"All nine patients showed brain MRI abnormalities, but only one had epilepsy."

Brain structure is abnormal in all characterized patients.

Reduced or Aberrant U5B snRNP Pool

Alternative to target-specific mis-splicing. Cellular quality-control pathways degrade defective snRNAs, including disease-mutant snRNAs, before they assemble into spliceosomes; when that control fails, defective snRNAs form aberrant spliceosomes that alter splicing. Applied to RNU5B-1, a loop I variant could either lower the amount of functional U5B snRNP or, if it escapes degradation, impair spliceosomes broadly rather than redirect them to a defined target set. This has been shown for U4-2 mutants, not for U5 variants, and neither the level nor the spliceosome incorporation of mutant U5B-1 has been measured.

Loss of functional U5B snRNP or broad spliceosome poisoning

U5 snRNP GO:0005682

Downstream

Abnormal Brain Development

Show evidence (2 references)

PMID:42562572 SUPPORT INDIRECT In vitro / ex vivo

"These pathways also repress mutant snRNAs associated with human developmental disorders."

Disease-mutant snRNAs are targeted by quality control. The mutants tested were U4-2, not U5, so this applies to RNU5B-1 by analogy.

PMID:42562572 SUPPORT INDIRECT In vitro / ex vivo

"Impeding snRNA quality control causes formation of aberrant spliceosomes and altered pre-mRNA splicing."

A stabilized defective snRNA can poison spliceosomes, the dominant-negative branch of this alternative.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Cardiovascular 1

Cardiac malformation Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."

Cardiac malformation in two of nine patients.

Eye 1

Eye abnormalities Abnormality of the eye HP:0000478

Coarse binding: variable spectrum

Show evidence (2 references)

PMID:40379786 SUPPORT Human clinical

"Three had ocular abnormalities, such as congenital glaucoma (n = 1), small papillae with retinal vascular tortuosity (n = 1) and severe myopia (<−12.25 D)."

Lists the different eye anomalies in three of nine patients.

PMID:40442284 SUPPORT Human clinical

"abnormality of the eye (OR = 18.7, P = 1.4 × 10−3)"

Eye anomalies are enriched in RNU5B-1 cases.

Head and Neck 3

Macrocephaly HP:0000256

Head size varies: two carriers of n.39C>G had macrocephaly and three carriers of n.44A>G had acquired microcephaly.

Show evidence (3 references)

PMID:40442284 SUPPORT Human clinical

"macrocephaly (OR = 30.6, P = 1.8 × 10−4)"

Macrocephaly is enriched in RNU5B-1 cases.

PMID:40379786 SUPPORT Human clinical

"Acquired microcephaly was noted in three individuals with n.44A>G, whereas two individuals with n.39C>G had macrocephaly."

Macrocephaly in two carriers of n.39C>G.

PMID:42502410 SUPPORT Human clinical

"macrocephaly (RNU5B-1) | – | 100.0% (1/1)"

The single RNU5B-1 patient in this cohort had macrocephaly.

Acquired microcephaly Secondary microcephaly HP:0005484

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Acquired microcephaly was noted in three individuals with n.44A>G"

Acquired microcephaly occurs with the n.44A>G variant.

Tooth agenesis HP:0009804

The source groups tooth agenesis with tooth fusion; the binding covers agenesis only.

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."

Dental anomalies in two of nine patients.

Musculoskeletal 3

Generalized hypotonia HP:0001290

Show evidence (1 reference)

PMID:40442284 SUPPORT Human clinical

"Generalized hypotonia (OR = 37.3, P = 7.4 × 10−5)"

Hypotonia is enriched in RNU5B-1 cases compared with other rare-disease probands.

Pectus excavatum HP:0000767

Show evidence (2 references)

PMID:40379786 SUPPORT Human clinical

"Three had pectus excavatum, two of whom also had marfanoid habitus."

Pectus excavatum in three of nine patients.

PMID:42502410 SUPPORT Human clinical

"pectus excavatum (RNU5B-1) | – | 100.0% (1/1)"

The single RNU5B-1 patient in this cohort had pectus excavatum.

Sacrococcygeal anomalies Abnormality of the skeletal system HP:0000924

Coarse binding: source unspecified

The source reports "sacrococcygeal abnormalities" without describing them. HPO has no term for the sacrococcygeal region as a whole, and the finding could be skin (a dimple, as in the RNU5A-1 patient reported alongside) as well as bone, so the skeletal binding is provisional.

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."

Sacrococcygeal anomalies in two of nine patients.

Nervous System 3

Global developmental delay FREQUENT HP:0001263

Show evidence (2 references)

PMID:40442284 SUPPORT Human clinical

"RNU5B-1-related disorder is characterized by global developmental delay, hypotonia, macrocephaly and failure to thrive."

Developmental delay is a core feature.

PMID:40379786 SUPPORT Human clinical

"Six had severe developmental delay, one had moderate developmental delay and one had normal cognition but attention difficulties."

Severity of delay among nine characterized patients; one had normal cognition.

Seizures HP:0001250

Reported frequency differs between reports. Seizures are enriched among RNU5B-1 cases in Genomics England data (used by both Jackson et al. and Nava et al., so the two are not independent) and feature in the five individuals characterized by Jackson et al., but only one of the nine individuals characterized by Nava et al. had epilepsy, so no frequency is assigned.

Show evidence (2 references)

PMID:40442284 SUPPORT Human clinical

"the ‘RNU5B-1-related disorder’ is characterized by global developmental delay, relative macrocephaly, seizures and failure to thrive"

Seizures are a feature in the characterized cohort.

PMID:40379786 SUPPORT Human clinical

"Human phenotype ontology terms enriched in RNU5B-1 cases from GEL include seizures, macrocephaly and eye anomalies"

Seizures are enriched in RNU5B-1 cases in Genomics England.

Abnormal brain morphology VERY_FREQUENT HP:0012443

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"All nine patients showed brain MRI abnormalities"

Brain MRI is abnormal in all characterized patients.

Respiratory 1

Pulmonary anomalies Abnormality of the respiratory system HP:0002086

Coarse binding: source unspecified

The source reports "pulmonary issues" without saying whether they were structural or functional, so a broad respiratory term is bound.

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."

Pulmonary anomalies in two of nine patients.

Growth 2

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:40442284 SUPPORT Human clinical

"failure to thrive (OR = 24.7, P = 4.5 × 10−4)"

Failure to thrive is enriched in RNU5B-1 cases.

Marfanoid habitus Disproportionate tall stature HP:0001519

Show evidence (1 reference)

PMID:40379786 SUPPORT Human clinical

"Three had pectus excavatum, two of whom also had marfanoid habitus."

Marfanoid habitus in two of nine patients.

🧬

Genetic Associations

1

RNU5B-1 (Causative heterozygous variants in the U5 5' loop I region.)

Gene: RNU5B-1 hgnc:10212 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:40379786 SUPPORT Human clinical

"This study establishes RNU5B-1 as a neurodevelopmental disorder gene"

Establishes the gene-disease relationship.

PMID:40442284 SUPPORT Human clinical

"we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, RNU2-2 and RNU5B-1"

Concurrent report of RNU5B-1 as an NDD gene, drawing partly on the same Genomics England data as Nava et al.

PMID:40968615 SUPPORT Human clinical

"one case with an unreported RNU5B-1 variant (n.38C>T)"

An additional de novo RNU5B-1 variant in a Chinese NDD cohort.

🔬

Diagnosis

1

Genome sequencing

RNU5B-1 is a short noncoding gene not captured by standard exome designs, so variants are found by genome sequencing or by exome designs extended to snRNA loci.

Show evidence (1 reference)

PMID:42502410 SUPPORT Human clinical

"Pathogenic variants in small nuclear RNA (snRNA) genes have recently emerged as a major cause of Mendelian disorders, particularly neurodevelopmental disorders, yet they remain difficult to detect in routine diagnostics because conventional whole-exome sequencing (WES) does not capture snRNA loci."

Explains why genome or snRNA-extended exome sequencing is required.

{ }

Source YAML

click to show

name: RNU5B-1 Related Neurodevelopmental Disorder With Seizures And Joint Laxity
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
  A dominant neurodevelopmental disorder caused by heterozygous, usually de novo
  variants in RNU5B-1, one of the genes encoding U5 small nuclear RNA of the major
  spliceosome. Pathogenic variants cluster in the invariant 5' loop I of U5, the
  element that base-pairs with exon sequence at the splice junction and holds the
  two exons in register for ligation. Affected individuals have global
  developmental delay, hypotonia, failure to thrive, seizures, eye anomalies and
  a variable set of congenital malformations. Head size varies: two carriers of
  n.39C>G had macrocephaly and three carriers of n.44A>G had acquired
  microcephaly. Variants are invisible to
  standard exome capture and are found by genome sequencing. Which of the splicing
  changes caused by these variants produce the neurodevelopmental phenotype is not
  known.
disease_term:
  preferred_term: RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity
  term:
    id: MONDO:1060179
    label: RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity
synonyms:
- NEDSJL
- RNU5B-1-related disorder
- neurodevelopmental disorder with seizures and joint laxity
parents:
- Neurodevelopmental Disorder
- Spliceosomopathy
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous variants, almost always de novo. Of seven phased loop I variants,
    five arose on the maternal allele and two on the paternal allele.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six NDD probands had five de novo variants in RNU5B-1, compared to a single de novo variant in a non-NDD individual"
    explanation: >-
      De novo heterozygous RNU5B-1 variants are enriched in neurodevelopmental
      disorder probands relative to other rare-disease participants.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the phaseable RNU5B-1 variants located in the U5 5′ loop I, five (n.39C>G, n.42_43insA and three n.44A>G) were phased to the maternal allele, while two (n.39C>G and n.37G>C) were on the paternal allele."
    explanation: >-
      Reports the parental origin of phased loop I variants (five maternal, two
      paternal).
pathophysiology:
- name: RNU5B-1 Loop I Variant
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    A heterozygous de novo single-nucleotide substitution or small insertion in a
    roughly 8-nucleotide stretch (about n.37 to n.44) of RNU5B-1 that encodes the
    invariant 5' loop I of U5 snRNA. The stretch is depleted of variation in gnomAD
    and UK Biobank but not variant-free: a different substitution, n.39C>T, is
    present in three gnomADv4 individuals. Recurrent variants are n.39C>G,
    n.42_43insA and n.44A>G. RNU5B-1 and RNU5A-1 are the main U5 genes expressed
    in brain.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: RNU5B-1
    term:
      id: hgnc:10212
      label: RNU5B-1
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of these variants (14 patients) clustered within a small region spanning chr15(hg38): 65,304,713–65,304,720, corresponding to the highly conserved U5 5′ loop I"
    explanation: Localizes the pathogenic variants to U5 loop I.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three variants (n.39C>G, n.42_43insA and n.44AG) were recurrent, identified in six, three and four patients, respectively."
    explanation: Names the recurrent variants.
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For RNU5B-1, we found three DN variants in a constrained region (from 30 to 50 bp; ENST00000363286.1:n.37G>C, n.42_43insA and n.44A>G) in four individuals"
    explanation: >-
      Places de novo variants in the same constrained region. This 100,000 Genomes
      Project cohort overlaps the Genomics England arm of Nava et al.
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, a different substitution in the constrained region, n.39C>T, is observed in three individuals in gnomADv4."
    explanation: Shows the constrained region is not variant-free in the general population.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As RNU5A-1 and RNU5B-1 are the main genes encoding U5 in the brain"
    explanation: >-
      RNU5B-1 is one of the two U5 genes predominantly expressed in brain; Nava et
      al. use this to focus on these two genes.
  downstream:
  - target: Perturbed U5 Loop I Exon Alignment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40442284
      reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "The RNU5B-1 variant positions lie within the invariantly conserved loop I structure of U5, essential for holding and aligning the two exons for accurate joining during splicing"
      explanation: >-
        The variants alter the nucleotides that perform exon alignment, so the
        variant directly changes this function. The effect is inferred from
        structure and has not been measured for the human variants.
  - target: Reduced or Aberrant U5B snRNP Pool
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - rnu5b1_snrna_qc_loss_or_poisoning
- name: Perturbed U5 Loop I Exon Alignment
  description: >-
    U5 loop I base-pairs with the last nucleotides of the upstream exon,
    contributing to 5' splice-site selection, and holds both exons in register for
    exon ligation. A variant U5 snRNA
    incorporated into spliceosomes is expected to change which exon-boundary
    sequences pair well with loop I. Whether the mutant snRNA acts by dominant
    negative or altered-function effect, rather than by loss of function, has not
    been tested.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: U5 loop I exon recognition and alignment during splicing
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: U5 snRNP
    term:
      id: GO:0005682
      label: U5 snRNP
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "U5 aligns exons by binding the 5′ and 3′ splice sites, ensuring precise ligation"
    explanation: States the normal function of U5 that the variants perturb.
  - reference: PMID:39809319
    reference_title: "RNA splicing: a split consensus reveals two major 5' splice site classes."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Later, related approaches demonstrated that loop 1 of U5 snRNA base paired to exon sequence upstream of the 5′ splice site and that this was important for 5′ splice site selection"
    explanation: >-
      Loop I pairing with the upstream exon contributes to 5' splice site choice,
      so changing loop I sequence would be expected to shift splice-site selection.
  downstream:
  - target: Variant-Specific Altered Splice Site Usage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39809319
      reference_title: "RNA splicing: a split consensus reveals two major 5' splice site classes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Indeed, the two classes can be defined by a preferential base-pairing interaction potential with either U5 snRNA loop 1 (AG//GUNNN) or the U6 snRNA ACAGA box (NN//GURAG)"
      explanation: >-
        A class of human 5' splice sites depends on pairing with U5 loop 1, so a
        loop I variant would be expected to shift usage within that class. This is a
        model from normal spliceosome biology, not a measurement in patients.
- name: Variant-Specific Altered Splice Site Usage
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  description: >-
    In cultured lymphocytes from six individuals with U5 variants (four RNU5B-1),
    the variants did not reproduce the 5' splice-site signature of ReNU syndrome
    and shared no common 5' or 3' splice-site signature with each other. Analysed
    one at a time, RNU5B-1 n.39C>G possibly altered mainly 5' splice-site usage and
    n.44A>G mainly 3' splice-site usage; the authors call these possible
    variant-specific effects. The affected genes, and which events matter in brain,
    are not known.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mRNA 5'-splice site recognition
    term:
      id: GO:0000395
      label: mRNA 5'-splice site recognition
    modifier: ABNORMAL
  - preferred_term: mRNA 3'-splice site recognition
    term:
      id: GO:0000389
      label: mRNA 3'-splice site recognition
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed possible variant-specific effects—RNU5B-1 n.39C>G mainly affected 5′SS, while RNU5B-1 n.44A>G primarily impacted 3′SS"
    explanation: Patient RNA-seq showing which class of splice site each recurrent variant affects.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These variants did not share the RNU4-2 5′SS signature (Extended Data Fig. 6e), and unlike RNU4-2 variants, RNU5 variants lacked a shared 5′SS or 3′SS signature."
    explanation: Establishes that there is no common splicing signature across U5 variants.
  downstream:
  - target: Abnormal Brain Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rnu5b1_missplicing_drives_brain_phenotype
- name: Abnormal Brain Development
  description: >-
    Structural brain abnormality is found on MRI in essentially every characterized
    patient, together with developmental delay. The mis-spliced transcripts that
    link the U5 defect to abnormal brain development have not been identified.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All nine patients showed brain MRI abnormalities, but only one had epilepsy."
    explanation: Brain structure is abnormal in all characterized patients.
  downstream:
  - target: Global developmental delay
  - target: Seizures
  - target: Abnormal brain morphology
  - target: Generalized hypotonia
  - target: Macrocephaly
  - target: Acquired microcephaly
- name: Reduced or Aberrant U5B snRNP Pool
  description: >-
    Alternative to target-specific mis-splicing. Cellular quality-control
    pathways degrade defective snRNAs, including disease-mutant snRNAs, before
    they assemble into spliceosomes; when that control fails, defective snRNAs
    form aberrant spliceosomes that alter splicing. Applied to RNU5B-1, a loop I
    variant could either lower the amount of functional U5B snRNP or, if it
    escapes degradation, impair spliceosomes broadly rather than redirect them
    to a defined target set. This has been shown for U4-2 mutants, not for U5
    variants, and neither the level nor the spliceosome incorporation of mutant
    U5B-1 has been measured.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: U5 snRNP
    term:
      id: GO:0005682
      label: U5 snRNP
  evidence:
  - reference: PMID:42562572
    reference_title: "Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "These pathways also repress mutant snRNAs associated with human developmental disorders."
    explanation: >-
      Disease-mutant snRNAs are targeted by quality control. The mutants tested
      were U4-2, not U5, so this applies to RNU5B-1 by analogy.
  - reference: PMID:42562572
    reference_title: "Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Impeding snRNA quality control causes formation of aberrant spliceosomes and altered pre-mRNA splicing."
    explanation: >-
      A stabilized defective snRNA can poison spliceosomes, the dominant-negative
      branch of this alternative.
  downstream:
  - target: Abnormal Brain Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rnu5b1_snrna_qc_loss_or_poisoning
mechanistic_hypotheses:
- hypothesis_group_id: rnu5b1_missplicing_drives_brain_phenotype
  hypothesis_label: Variant-specific mis-splicing of neurodevelopmental transcripts
  status: EMERGING
  description: >-
    The phenotype is caused by altered splice-site usage in a set of transcripts
    needed for brain development, with the set differing by variant according to
    which exon-boundary sequences pair with the mutant loop I. The loop I pairing
    part is an inference from normal spliceosome biology (PMID:39809319), not a
    model the disease papers propose. No such transcript has been identified, and
    the splicing data come from cultured lymphocytes of four RNU5B-1 carriers.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results, although obtained from a limited number of patients, may underline the clinical variability observed for patients with RNU5 variants."
    explanation: >-
      The authors propose that the variant-specific splicing effects explain the
      clinical variability, while stating the data are limited.
- hypothesis_group_id: rnu5b1_snrna_qc_loss_or_poisoning
  hypothesis_label: Loss of functional U5B snRNP or broad spliceosome poisoning
  status: ALTERNATIVE
  description: >-
    The phenotype follows from too little functional U5B snRNP, because the
    mutant snRNA is degraded by quality control, or from mutant U5B snRNP that
    assembles and impairs splicing broadly. Either predicts diffuse splicing
    disruption rather than a variant-specific target set. The evidence is from
    U4-2 mutants in cultured cells; a pure loss-of-function reading must also
    explain why heterozygous loss of one of several brain-expressed U5 genes
    would cause disease.
  evidence:
  - reference: PMID:42562572
    reference_title: "Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Here, we identify multiple checkpoints in snRNA biogenesis monitored by quality control machineries that subject defective snRNAs to degradation and prevent their assembly into spliceosomes."
    explanation: >-
      Establishes the degradation route that would lower the functional U5B pool
      if mutant U5B-1 is recognized as defective.
phenotypes:
- name: Global developmental delay
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNU5B-1-related disorder is characterized by global developmental delay, hypotonia, macrocephaly and failure to thrive."
    explanation: Developmental delay is a core feature.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six had severe developmental delay, one had moderate developmental delay and one had normal cognition but attention difficulties."
    explanation: Severity of delay among nine characterized patients; one had normal cognition.
- name: Generalized hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized hypotonia (OR = 37.3, P = 7.4 × 10−5)"
    explanation: Hypotonia is enriched in RNU5B-1 cases compared with other rare-disease probands.
- name: Seizures
  category: Neurological
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    Reported frequency differs between reports. Seizures are enriched among
    RNU5B-1 cases in Genomics England data (used by both Jackson et al. and Nava et
    al., so the two are not independent) and feature in the five individuals
    characterized by Jackson et al., but only one of the nine individuals
    characterized by Nava et al. had epilepsy, so no frequency is assigned.
  evidence:
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the ‘RNU5B-1-related disorder’ is characterized by global developmental delay, relative macrocephaly, seizures and failure to thrive"
    explanation: Seizures are a feature in the characterized cohort.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human phenotype ontology terms enriched in RNU5B-1 cases from GEL include seizures, macrocephaly and eye anomalies"
    explanation: Seizures are enriched in RNU5B-1 cases in Genomics England.
- name: Macrocephaly
  category: Growth
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  notes: >-
    Head size varies: two carriers of n.39C>G had macrocephaly and three carriers
    of n.44A>G had acquired microcephaly.
  evidence:
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocephaly (OR = 30.6, P = 1.8 × 10−4)"
    explanation: Macrocephaly is enriched in RNU5B-1 cases.
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired microcephaly was noted in three individuals with n.44A>G, whereas two individuals with n.39C>G had macrocephaly."
    explanation: Macrocephaly in two carriers of n.39C>G.
  - reference: PMID:42502410
    reference_title: "Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocephaly (RNU5B-1) | – | 100.0% (1/1)"
    explanation: The single RNU5B-1 patient in this cohort had macrocephaly.
- name: Acquired microcephaly
  category: Growth
  phenotype_term:
    preferred_term: Acquired microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired microcephaly was noted in three individuals with n.44A>G"
    explanation: Acquired microcephaly occurs with the n.44A>G variant.
- name: Failure to thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive (OR = 24.7, P = 4.5 × 10−4)"
    explanation: Failure to thrive is enriched in RNU5B-1 cases.
- name: Abnormal brain morphology
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal brain MRI
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All nine patients showed brain MRI abnormalities"
    explanation: Brain MRI is abnormal in all characterized patients.
- name: Eye abnormalities
  category: Ophthalmological
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
    coarse_binding_basis: VARIABLE_SPECTRUM
  description: >-
    Reported eye findings are heterogeneous: congenital glaucoma, small optic
    papillae with retinal vascular tortuosity, and severe myopia.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three had ocular abnormalities, such as congenital glaucoma (n = 1), small papillae with retinal vascular tortuosity (n = 1) and severe myopia (<−12.25 D)."
    explanation: Lists the different eye anomalies in three of nine patients.
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormality of the eye (OR = 18.7, P = 1.4 × 10−3)"
    explanation: Eye anomalies are enriched in RNU5B-1 cases.
- name: Pectus excavatum
  category: Skeletal
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three had pectus excavatum, two of whom also had marfanoid habitus."
    explanation: Pectus excavatum in three of nine patients.
  - reference: PMID:42502410
    reference_title: "Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pectus excavatum (RNU5B-1) | – | 100.0% (1/1)"
    explanation: The single RNU5B-1 patient in this cohort had pectus excavatum.
- name: Marfanoid habitus
  category: Skeletal
  phenotype_term:
    preferred_term: Marfanoid habitus
    term:
      id: HP:0001519
      label: Disproportionate tall stature
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three had pectus excavatum, two of whom also had marfanoid habitus."
    explanation: Marfanoid habitus in two of nine patients.
- name: Tooth agenesis
  category: Craniofacial
  phenotype_term:
    preferred_term: Tooth agenesis or fusion
    term:
      id: HP:0009804
      label: Tooth agenesis
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."
    explanation: Dental anomalies in two of nine patients.
  notes: >-
    The source groups tooth agenesis with tooth fusion; the binding covers
    agenesis only.
- name: Cardiac malformation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Cardiac malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."
    explanation: Cardiac malformation in two of nine patients.
- name: Pulmonary anomalies
  category: Respiratory
  phenotype_term:
    preferred_term: Pulmonary issues
    term:
      id: HP:0002086
      label: Abnormality of the respiratory system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  notes: >-
    The source reports "pulmonary issues" without saying whether they were
    structural or functional, so a broad respiratory term is bound.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."
    explanation: Pulmonary anomalies in two of nine patients.
- name: Sacrococcygeal anomalies
  category: Skeletal
  phenotype_term:
    preferred_term: Sacrococcygeal abnormality
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  notes: >-
    The source reports "sacrococcygeal abnormalities" without describing them.
    HPO has no term for the sacrococcygeal region as a whole, and the finding
    could be skin (a dimple, as in the RNU5A-1 patient reported alongside) as
    well as bone, so the skeletal binding is provisional.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other malformations included pulmonary issues (n = 2), sacrococcygeal abnormalities (n = 2), tooth agenesis or fusion (n = 2) and cardiac malformation (n = 2)."
    explanation: Sacrococcygeal anomalies in two of nine patients.
genetic:
- name: RNU5B-1
  gene_term:
    preferred_term: RNU5B-1
    term:
      id: hgnc:10212
      label: RNU5B-1
  association: >-
    Causative heterozygous variants in the U5 5' loop I region.
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study establishes RNU5B-1 as a neurodevelopmental disorder gene"
    explanation: Establishes the gene-disease relationship.
  - reference: PMID:40442284
    reference_title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, RNU2-2 and RNU5B-1"
    explanation: >-
      Concurrent report of RNU5B-1 as an NDD gene, drawing partly on the same
      Genomics England data as Nava et al.
  - reference: PMID:40968615
    reference_title: "Reanalysis of Whole Genome Sequencing Resolves Genetically Undiagnosed Patients With \"RNUopathies\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one case with an unreported RNU5B-1 variant (n.38C>T)"
    explanation: An additional de novo RNU5B-1 variant in a Chinese NDD cohort.
diagnosis:
- name: Genome sequencing
  description: >-
    RNU5B-1 is a short noncoding gene not captured by standard exome designs, so
    variants are found by genome sequencing or by exome designs extended to snRNA
    loci.
  evidence:
  - reference: PMID:42502410
    reference_title: "Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in small nuclear RNA (snRNA) genes have recently emerged as a major cause of Mendelian disorders, particularly neurodevelopmental disorders, yet they remain difficult to detect in routine diagnostics because conventional whole-exome sequencing (WES) does not capture snRNA loci."
    explanation: Explains why genome or snRNA-extended exome sequencing is required.
discussions:
- discussion_id: rnu5b1_which_splicing_errors_cause_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Variant-Specific Altered Splice Site Usage
  - pathophysiology#Reduced or Aberrant U5B snRNP Pool
  - pathophysiology#Abnormal Brain Development
  prompt: >-
    Which splicing errors caused by RNU5B-1 loop I variants produce the
    neurodevelopmental phenotype?
  rationale: >-
    The only patient splicing data come from cultured lymphocytes of four RNU5B-1
    carriers. These
    showed no shared 5' or 3' splice-site signature, unlike ReNU syndrome, and the
    two recurrent variants appeared to act differently: n.39C>G mainly on 5' splice
    sites, n.44A>G mainly on 3' splice sites. No affected transcript has been tied
    to a neurodevelopmental gene, there are no neural RNA data, and the clinical
    picture may differ by variant (macrocephaly in two n.39C>G carriers, acquired
    microcephaly in three n.44A>G carriers). Whether the mutant U5 acts by dominant negative or
    altered-function effect has not been tested. A loop I model predicts that each
    variant re-weights splice sites whose upstream-exon sequence pairs with the
    mutant loop, which would make the target set variant-specific and could explain
    the clinical heterogeneity; that prediction is untested. A competing model
    holds that quality control degrades the mutant snRNA or that a stabilized
    mutant poisons spliceosomes broadly, which predicts diffuse rather than
    variant-specific disruption; measuring the level and spliceosome
    incorporation of mutant U5B-1 separates the two.
  evidence:
  - reference: PMID:40379786
    reference_title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results, although obtained from a limited number of patients, may underline the clinical variability observed for patients with RNU5 variants."
    explanation: The authors state that the splicing data are limited.
  proposed_experiments:
  - experiment_id: rnu5b1_neuronal_splicing_by_variant
    name: Splicing profiles of RNU5B-1 variants in human neural cells
    description: >-
      Introduce n.39C>G, n.42_43insA, n.44A>G and n.37G>C, each heterozygous, into an
      isogenic human iPSC line, differentiate to neural progenitors and cortical
      neurons, and profile splicing by deep RNA-seq with and without NMD inhibition.
      Compare each variant against the isogenic control and against each other, and
      test whether altered 5' splice sites are enriched for upstream-exon sequences
      predicted to pair differently with the mutant loop I. Because U5 is encoded by
      several genes, first confirm by allele-specific small RNA-seq that the
      mutant U5B-1 is expressed in neurons and incorporated into spliceosomes.
    would_support:
    - mechanistic_hypotheses#rnu5b1_missplicing_drives_brain_phenotype
    would_refute:
    - mechanistic_hypotheses#rnu5b1_missplicing_drives_brain_phenotype
    supporting_outcome:
    - >-
      Each variant produces a reproducible, variant-specific set of altered splice
      sites in neural cells, enriched for loop I pairing changes and for genes with
      established roles in brain development.
    refuting_outcome:
    - >-
      No reproducible splicing change beyond control variability in neural cells,
      or changes unrelated to loop I pairing, which would point to another
      mechanism such as altered snRNP biogenesis.
    evidence:
    - reference: PMID:42856368
      reference_title: "A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In a patient-derived induced pluripotent stem cell (iPSC) model of the recurrent RNU4-2 n.64_64insT variant, the splicing signature was fully recapitulated across all stages of differentiation into cortical neuron-like cells."
      explanation: >-
        Shows the design is feasible in the sibling disorder: a blood splicing
        signature carried over to iPSC-derived cortical neurons. Preprint, and
        about RNU4-2, not RNU5B-1.
  - experiment_id: rnu5b1_mutant_u5_fate
    name: Level and spliceosome incorporation of mutant U5B-1
    description: >-
      In patient lymphoblastoid cells and in the isogenic iPSC-derived neurons
      above, measure mature U5B-1 by allele-specific small RNA-seq or primer
      extension, compare with RNU5A-1 and total U5, and test whether mutant
      U5B-1 is found in U5 snRNP, tri-snRNP and spliceosome fractions by
      affinity purification or glycerol-gradient fractionation followed by
      allele-specific sequencing. Repeat with quality-control factors such as
      the NEXT-exosome or TUT4/7 depleted to see whether mutant U5B-1 is being
      degraded.
    would_support:
    - mechanistic_hypotheses#rnu5b1_snrna_qc_loss_or_poisoning
    would_refute:
    - mechanistic_hypotheses#rnu5b1_snrna_qc_loss_or_poisoning
    supporting_outcome:
    - >-
      Mutant U5B-1 is depleted relative to the wild-type allele and recovers when
      quality control is inhibited, or it is incorporated but splicing changes
      are broad rather than variant-specific.
    refuting_outcome:
    - >-
      Mutant U5B-1 accumulates at wild-type levels and is incorporated into
      spliceosomes, which leaves altered splice-site selection by the mutant
      loop as the more likely mechanism.
    evidence:
    - reference: PMID:42562572
      reference_title: "Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These pathways also repress mutant snRNAs associated with human developmental disorders."
      explanation: >-
        Motivates measuring mutant U5B-1 stability directly, since disease-mutant
        snRNAs can be degraded by these pathways.
references:
- reference: PMID:40379786
  title: "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption."
- reference: PMID:40442284
  title: "Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes."
- reference: PMID:40968615
  title: "Reanalysis of Whole Genome Sequencing Resolves Genetically Undiagnosed Patients With \"RNUopathies\"."
- reference: PMID:42502410
  title: "Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening."
- reference: PMID:39809319
  title: "RNA splicing: a split consensus reveals two major 5' splice site classes."
- reference: PMID:42562572
  title: "Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes."
- reference: PMID:42856368
  title: "A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome."
notes: >-
  No GeneReviews chapter names this disorder. Joint laxity is in the MONDO and
  OMIM (#621302) name but is not documented for RNU5B-1 in the primary reports:
  Nava et al. tabulate joint hyperlaxity only for RNU4-2 patients, and the single
  RNU5B-1 patient in PMID:42502410 did not have it. It is therefore not curated as
  a phenotype here. No disease-specific treatment has been reported; care is
  supportive.

📚

References & Deep Research

References

7

PMID:40379786

Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption.

No top-level findings curated for this source.

PMID:40442284

Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes.

No top-level findings curated for this source.

PMID:40968615

Reanalysis of Whole Genome Sequencing Resolves Genetically Undiagnosed Patients With "RNUopathies".

No top-level findings curated for this source.

PMID:42502410

Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening.

No top-level findings curated for this source.

PMID:39809319

RNA splicing: a split consensus reveals two major 5' splice site classes.

No top-level findings curated for this source.

PMID:42562572

Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.

No top-level findings curated for this source.

PMID:42856368

A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: RNU5B-1_Related_Neurodevelopmental_Disorder_With_Seizures_And_Joint_Laxity · 2026-10-15T15:52:05Z · View source

New entry for MONDO:1060179, curated from the stub of the same name (stub deleted). Primary sources: Nava et al. 2025 (PMID:40379786) and Jackson et al. 2025 (PMID:40442284), read in full text; supporting: PMID:40968615 (Chinese WGS reanalysis, n.38C>T), PMID:42502410 (snRNA-extended exome), PMID:39809319 (review of U5 loop 1 and the two 5' splice-site classes). Deep research: falcon was requested but Edison returned 503 'Failed to authenticate' twice, including with --fallback, so the claude_code provider report was used; it passed preflight-dr (RNU5B-1 mentioned 24 times; OMIM 621302 matches the MONDO xref). Its one unmatched quote (PMC12165836, 'is highly likely to have arisen on the maternal allele') was not used. The pathograph runs variant -> perturbed loop I exon alignment -> variant-specific splice-site changes -> abnormal brain development -> phenotypes. The splicing-to-brain edge is tagged as an EMERGING hypothesis because no mis-spliced neurodevelopmental transcript has been identified. A KNOWLEDGE_GAP discussion records which splicing errors cause the phenotype, with a proposed isogenic iPSC-neuron experiment. Joint hypermobility (in the MONDO name and definition) has no quotable RNU5B-1 source and carries no evidence. Validated with just validate, validate-terms, count-verified-snippets (35/35), check-entity-refs, check-causal-targets, check-coarse-phenotypes, check-reference-titles and validate-disorders (0 issues).

Claude Code ▸

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

claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-15T15:44:53.255149

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.

Phenotype	Evidence	Suggested HPO (verify)
Global developmental delay / intellectual disability	Of nine RNU5B-1 patients with detailed data, six had severe delay, one moderate, and one normal cognition with attention difficulties (Nava). In Jackson, GDD had OR 22.1.	Global developmental delay (HP:0001263); Intellectual disability
Generalized hypotonia	Jackson: OR 37.3, P = 7.4×10⁻⁵ vs rare-disease probands	Generalized hypotonia
Macrocephaly	Jackson: OR 30.6. Nava: macrocephaly in two n.39C>G carriers.	Macrocephaly
Acquired microcephaly	Nava: three n.44A>G carriers	Acquired microcephaly
Failure to thrive	Jackson: OR 24.7	Failure to thrive
Brain MRI abnormality	Nava: all 9 patients	Abnormal brain MRI
Seizures	Nava: "All nine patients showed brain MRI abnormalities, but only one had epilepsy." Jackson also describes seizures among the five individuals with detailed data.	Seizure
Pectus excavatum	Nava: 3 of 9, two also marfanoid	Pectus excavatum; Marfanoid habitus
Eye abnormalities	Jackson: OR 18.7. Nava: 3 patients.	Abnormality of the eye
Other malformations	Nava: pulmonary (2), sacrococcygeal (2), tooth agenesis or fusion (2), cardiac (2)
Joint hypermobility	Named in the disease title via OMIM; not reported for RNU5 patients in Nava. Unverified.	Joint hypermobility

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):

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).
The variant changes the sequence of U5 snRNA loop I. The sequence is invariantly conserved and binds and aligns exons during splicing.
In the spliceosome, altered loop I disrupts exon alignment. Nava note that "U5 loop I is crucial for 5′SS transfer."
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.
Mis-splicing of many transcripts is thought to impair brain development. The specific genes involved are unknown.
The outcome is the neurodevelopmental phenotype (delay, hypotonia, head-size change, MRI abnormalities, seizures in a minority).
Expression. Jackson report high RNU5B-1 expression in developing brain and retina (ENCODE small RNA-seq). This is consistent with the neural phenotype.
Functional evidence level. Jackson report no direct functional assays of RNU5B-1. Nava provide limited transcriptomic data from small patient numbers.
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.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	6
On topic	5
Off topic	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.

Outcome	Count
Terms checked	2
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	1
Terms named as a different term	0

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

RNU5B-1 Related Neurodevelopmental Disorder With Seizures And Joint Laxity

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References

Deep Research

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

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Citations

Curation Recommendations

Reference Validation

Quotes not found in the cited source

Term Validation