RNU4ATAC spectrum disorder (RNU4atac-opathy)

name: RNU4ATAC Spectrum Disorder
display_name: RNU4ATAC spectrum disorder (RNU4atac-opathy)
creation_date: "2026-10-26T00:00:00Z"
description: >-
  RNU4ATAC spectrum disorder ("RNU4atac-opathy") is the autosomal recessive
  phenotypic spectrum caused by biallelic pathogenic variants in RNU4ATAC, the
  non-protein-coding gene for U4atac small nuclear RNA of the minor
  (U12-dependent) spliceosome. Loss of U4atac function impairs excision of the
  minor introns present in several hundred human genes. The spectrum spans
  three historically separate clinical phenotypes: microcephalic
  osteodysplastic primordial dwarfism type I/III (MOPD I, Taybi-Linder
  syndrome) at the severe, usually lethal end, and Roifman syndrome and
  Lowry-Wood syndrome at the milder end, with survival into adulthood. Growth
  restriction, microcephaly, skeletal dysplasia and cognitive impairment are
  common to all three. The radiographic pattern differs between them
  (spondyloepimetaphyseal, spondyloepiphyseal and multiple epiphyseal
  dysplasia respectively), as does the weight of immunodeficiency, retinal
  dystrophy and other organ involvement.
grouping_basis:
- SHARED_MECHANISM
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a shared gene and mechanism: every member is caused by biallelic
  RNU4ATAC variants that impair the minor spliceosome, and GeneReviews treats
  the members as one spectrum under a single diagnosis. The members stay as
  separate Disease entries rather than one merged entry because they differ in
  ways that change prognosis, surveillance and care. MOPD I is a severe
  primordial dwarfism with structural brain malformation, energy-related
  strokes and death in infancy or early childhood in most reported cases.
  Roifman syndrome is a spondyloepiphyseal dysplasia whose course is often
  dominated by antibody deficiency, immune dysregulation and retinal
  dystrophy, and which needs immunoglobulin replacement and immunological
  care. Lowry-Wood syndrome is a multiple epiphyseal dysplasia with
  microcephaly and nystagmus. The ISDS 2023 nosology also lists the three in
  different groups. The genotype explains much of the split: variants
  confined to the 5' stem-loop of U4atac give MOPD I, while genotypes with at
  least one variant that spares the 5' stem-loop give the milder phenotypes.
  The boundary is not sharp. Many patients have features of more than one
  named phenotype, and siblings with the same genotype can differ, so this is
  a grouping over named phenotypes, not a claim that every patient falls
  cleanly into one of them.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100558
      label: RNU4ATAC spectrum disorder
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping is the union of the RNU4ATAC phenotypes, which is what the
      MONDO class names. Its three MONDO descendants are microcephalic
      osteodysplastic primordial dwarfism type I (MONDO:0008871), Roifman
      syndrome (MONDO:0014722) and Lowry-Wood syndrome (MONDO:0009191), and
      all three are members here.
membership_criteria:
- description: >-
    A disorder belongs to the RNU4ATAC spectrum if and only if it is caused by
    biallelic pathogenic variants in RNU4ATAC. The gene defines the spectrum,
    so the criterion is both necessary and sufficient.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: HAS_GENE
    description: Biallelic pathogenic variants in RNU4ATAC (U4atac snRNA).
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
  evidence:
  - reference: PMID:36795902
    reference_title: "RNU4atac-opathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNU4atac-opathy encompasses the phenotypic spectrum of biallelic RNU4ATAC
      pathogenic variants, including the three historically designated
      clinical phenotypes microcephalic osteodysplastic primordial dwarfism
      type I/III (MOPDI), Roifman syndrome, and Lowry-Wood syndrome
    explanation: >-
      GeneReviews defines the spectrum by the gene and names the three
      phenotypes this grouping spans.
members:
- member: Microcephalic Osteodysplastic Primordial Dwarfism Type I
  member_type: DISEASE
  display_name: MOPD I (Taybi-Linder syndrome)
  differentiating_mechanisms:
  - description: >-
      The severe end of the spectrum. Both variants fall in the 5' stem-loop
      of U4atac, the region where U4atac binds proteins it needs to assemble
      the minor-spliceosome tri-snRNP, so minor-intron splicing is badly
      impaired. The result is extreme intrauterine growth restriction, severe
      microcephaly with brain malformation, and a spondyloepimetaphyseal
      dysplasia. Most affected children die in infancy or early childhood.
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
    evidence:
    - reference: PMID:41808109
      reference_title: "Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Reevaluation of all previously published cases confirms the strong correlation of RNU4ATAC variants located exclusively at the 5’ stem-loop with severe lethal disease falling under MOPD1."
      explanation: >-
        A reevaluation of all published cases ties variants confined to the 5'
        stem-loop to the severe, lethal MOPD I phenotype.
    - reference: PMID:29265708
      reference_title: The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MOPDI/III is an SEMD, Roifman syndrome is an SED, and LWS is an MED."
      explanation: >-
        Gives the radiographic pattern that separates the three RNU4ATAC
        phenotypes: spondyloepimetaphyseal dysplasia in MOPD I.
- member: Roifman-syndrome
  member_type: DISEASE
  display_name: Roifman syndrome
  differentiating_mechanisms:
  - description: >-
      The milder end of the spectrum. At least one variant spares the 5'
      stem-loop, typically with the second variant in stem II, so some minor
      spliceosome function is kept. Patients have a spondyloepiphyseal
      dysplasia and survive into adulthood. Antibody deficiency, immune
      dysregulation and retinal dystrophy often shape the course, and
      immunological management is central to care.
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
    evidence:
    - reference: PMID:41808109
      reference_title: "Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genotypes carrying at least one variant that spares the 5′ stem-loop are associated with a milder phenotype and later onset."
      explanation: >-
        States the genotype rule that places Roifman syndrome, and the other
        milder phenotypes, apart from MOPD I.
    - reference: PMID:41808109
      reference_title: "Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        genotypes sparing the critical 5′ stem-loop region of RNU4ATAC can
        cause a complex phenotype that is not necessarily dominated by
        dysmorphic features or growth failure, but rather by immunodeficiency
        and immune dysregulation
      explanation: >-
        Supports immunodeficiency and immune dysregulation, rather than growth
        failure, as the features that dominate the milder genotypes.
- member: Lowry-Wood Syndrome
  member_type: DISEASE
  display_name: Lowry-Wood syndrome
  differentiating_mechanisms:
  - description: >-
      The mildest named phenotype. The reported variants are dispersed across
      U4atac at less conserved positions than MOPD I variants, and in a
      splicing assay Lowry-Wood alleles had the smallest functional effects.
      Patients have a multiple epiphyseal dysplasia without spinal involvement,
      with microcephaly and congenital nystagmus, variable short stature and
      intellectual disability, and at most subclinical antibody deficiency.
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
    evidence:
    - reference: PMID:30368667
      reference_title: "Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5' Stem-Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions"
      explanation: >-
        Places Lowry-Wood variants at less conserved, more dispersed positions
        than the 5' stem-loop variants of MOPD I.
    - reference: PMID:32628740
      reference_title: "Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "variants found in RFMN patients were globally associated with stronger effects than those identified in TALS patients, while those identified in LWS had the lowest effects"
      explanation: >-
        Lowry-Wood alleles had the smallest effect on minor intron splicing in
        a functional assay.
    - reference: PMID:29265708
      reference_title: The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MOPDI/III is an SEMD, Roifman syndrome is an SED, and LWS is an MED."
      explanation: >-
        Gives the radiographic pattern that separates the three RNU4ATAC
        phenotypes: multiple epiphyseal dysplasia in Lowry-Wood syndrome.
references:
- reference: PMID:36795902
  title: "RNU4atac-opathy."
  tags:
  - GeneReviews
notes: >-
  The stub for MONDO:0100558 was resolved as entry_type GROUPING because each of
  its three MONDO descendants (MOPD I, Roifman syndrome and Lowry-Wood
  syndrome) is curated as a separate Disease entry with its own pathograph, and
  a Disease entry for the spectrum would duplicate them.

  The gene criterion is NECESSARY_AND_SUFFICIENT because RNU4ATAC is bound in
  no other KB entry. If a future entry binds RNU4ATAC for a different reason,
  such as a differential or a modifier, revisit the sufficiency direction.
  This grouping is nested under the broader Spliceosomopathies grouping, which
  lists it as a GROUPING member in place of separate MOPD I and Roifman
  syndrome rows.