RNU12-related minor spliceopathy

Mendelian Pathograph 2 Genetic Disorder Neurodevelopmental Disorder Craniofacial Disorder

RNU12-related minor spliceopathy is a mechanism-defined Mendelian disease spectrum caused by biallelic pathogenic variants in RNU12, which encodes the U12 small nuclear RNA of the minor spliceosome. The shared molecular lesion is minor spliceosome dysfunction with defective splicing of U12-type introns in minor intron-containing genes. Reported clinical presentations currently include CDAGS syndrome and spinocerebellar ataxia, autosomal recessive 33 (SCAR33), which differ in organ predilection but share the same upstream spliceosomal defect.

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1
Inheritance
2
Pathophys.
7
Phenotypes
2
Pathograph
2
Subtypes
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34085356 SUPPORT Human Clinical
"Whole exome sequencing revealed biallelic rare variants that disrupt highly conserved nucleotides within the RNU12 gene."
Supports recessive inheritance for the CDAGS presentation by showing biallelic pathogenic variants in affected individuals.
PMID:27863452 SUPPORT Human Clinical
"whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age."
Supports recessive inheritance for the SCAR33 presentation.
◆

Subtypes

2
CDAGS syndrome MONDO:0011287
Multisystem developmental presentation characterized by craniosynostosis, delayed closure of the fontanelles and cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin manifestations including porokeratosis.
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations."
Defines the CDAGS clinical presentation associated with biallelic RNU12 variants.
Spinocerebellar ataxia, autosomal recessive 33 MONDO:0859360
Early-onset neurologic presentation dominated by cerebellar ataxia, delayed motor development, hypotonia, tremor, nystagmus, dysarthria, and cerebellar hypoplasia or degeneration.
Show evidence (1 reference)
PMID:27863452 SUPPORT Human Clinical
"WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia."
Establishes the RNU12-associated early-onset ataxia presentation that maps to SCAR33.
⚙

Pathophysiology

2
Minor spliceosome dysfunction from RNU12 variants
Biallelic RNU12 variants disrupt the U12 small nuclear RNA, a core RNA component of the minor spliceosome. This compromises minor spliceosome stability and function and impairs normal processing of U12-type introns.
RNU12 link
U12-type intron splicing link ↓ DECREASED
Downstream
U12-type intron retention and transcriptome dysregulation
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"RNU12 encodes a small nuclear RNA that is a component of the minor spliceosome and is essential for minor intron splicing."
Establishes that the disease gene encodes a core minor spliceosome RNA required for U12-type intron splicing.
U12-type intron retention and transcriptome dysregulation
Loss of normal minor spliceosome activity causes selective disruption of U12-type intron splicing with downstream transcriptome-wide dysregulation in minor intron-containing genes. Tissue-specific sensitivity to this shared splicing lesion likely determines whether the dominant presentation is cranio-cutaneous malformation or cerebellar neurodegeneration.
U12-type intron splicing link ↓ DECREASED
Show evidence (2 references)
PMID:27863452 SUPPORT Human Clinical
"Reverse transcriptase PCR demonstrated minor intron retention in all of 9 randomly selected RNAs from this group, and RNAseq showed splicing disruption specific to all U12-type introns detected in blood monocytes from affected individuals."
Demonstrates selective U12-type intron retention in the ataxia presentation.
PMID:34085356 SUPPORT In Vitro
"Whole transcriptome sequencing analysis of lymphoblastoid cells identified 120 differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events in the patient."
Extends the same splicing-dysregulation mechanism to the CDAGS presentation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RNU12-related minor spliceopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Genitourinary 1
Genitourinary malformation Abnormality of the genitourinary system (HP:0000119)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations."
Directly supports genitourinary malformations as part of the CDAGS acronym and clinical spectrum.
Head and Neck 1
Craniosynostosis Craniosynostosis (HP:0001363)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations."
Directly supports craniosynostosis as part of the CDAGS subtype.
Integument 1
Porokeratosis Abnormality of the skin (HP:0000951)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"These findings provide evidence of the involvement of RNU12 in craniosynostosis, anal and genitourinary patterning, and cutaneous disease."
Supports cutaneous disease as part of CDAGS; porokeratosis is the specific skin manifestation named in the syndrome.
Musculoskeletal 1
Clavicular hypoplasia Aplasia/Hypoplasia of the clavicles (HP:0006710)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations."
Directly supports clavicular hypoplasia as a defining feature of the CDAGS clinical presentation.
Nervous System 1
Early-onset cerebellar ataxia Ataxia (HP:0001251)
Show evidence (1 reference)
PMID:27863452 SUPPORT Human Clinical
"WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia."
Directly supports the defining ataxia phenotype of the SCAR33 subtype.
Other 2
Delayed closure of the anterior fontanelle Delayed closure of the anterior fontanelle (HP:0001476)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations."
Directly supports delayed fontanelle closure as part of the CDAGS acronym and clinical presentation.
Anal malformation Abnormality of the anus (HP:0004378)
Show evidence (1 reference)
PMID:34085356 SUPPORT Human Clinical
"These findings provide evidence of the involvement of RNU12 in craniosynostosis, anal and genitourinary patterning, and cutaneous disease."
Directly implicates RNU12 in anal patterning, supporting anal malformation as part of the CDAGS spectrum.
{ }

Source YAML

click to show 
name: RNU12-related minor spliceopathy
creation_date: "2026-04-16T00:00:00Z"
updated_date: "2026-04-19T00:00:00Z"
category: Mendelian
description: >-
  RNU12-related minor spliceopathy is a mechanism-defined Mendelian disease
  spectrum caused by biallelic pathogenic variants in RNU12, which encodes the
  U12 small nuclear RNA of the minor spliceosome. The shared molecular lesion is
  minor spliceosome dysfunction with defective splicing of U12-type introns in
  minor intron-containing genes. Reported clinical presentations currently
  include CDAGS syndrome and spinocerebellar ataxia, autosomal recessive 33
  (SCAR33), which differ in organ predilection but share the same upstream
  spliceosomal defect.
synonyms:
- RNU12-related minor spliceopathy disorder
- RNU12-related spliceopathy
parents:
- Genetic Disorder
- Neurodevelopmental Disorder
- Craniofacial Disorder
has_subtypes:
- name: CDAGS
  display_name: CDAGS syndrome
  description: >-
    Multisystem developmental presentation characterized by craniosynostosis,
    delayed closure of the fontanelles and cranial defects, clavicular
    hypoplasia, anal and genitourinary malformations, and skin manifestations
    including porokeratosis.
  subtype_term:
    preferred_term: craniosynostosis-anal anomalies-porokeratosis syndrome
    term:
      id: MONDO:0011287
      label: craniosynostosis-anal anomalies-porokeratosis syndrome
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDAGS Syndrome is a rare congenital disorder characterized by
      Craniosynostosis, Delayed closure of the fontanelles, cranial defects,
      clavicular hypoplasia, Anal and Genitourinary malformations, and Skin
      manifestations.
    explanation: >-
      Defines the CDAGS clinical presentation associated with biallelic RNU12
      variants.
- name: SCAR33
  display_name: Spinocerebellar ataxia, autosomal recessive 33
  description: >-
    Early-onset neurologic presentation dominated by cerebellar ataxia, delayed
    motor development, hypotonia, tremor, nystagmus, dysarthria, and cerebellar
    hypoplasia or degeneration.
  subtype_term:
    preferred_term: spinocerebellar ataxia, autosomal recessive 33
    term:
      id: MONDO:0859360
      label: spinocerebellar ataxia, autosomal recessive 33
  evidence:
  - reference: PMID:27863452
    reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WGS revealed a point mutation in noncoding RNA RNU12 that was associated
      with early onset cerebellar ataxia.
    explanation: >-
      Establishes the RNU12-associated early-onset ataxia presentation that maps
      to SCAR33.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed biallelic rare variants that disrupt
      highly conserved nucleotides within the RNU12 gene.
    explanation: >-
      Supports recessive inheritance for the CDAGS presentation by showing
      biallelic pathogenic variants in affected individuals.
  - reference: PMID:27863452
    reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole genome sequencing (WGS) was analyzed in a large consanguineous
      family in which members displayed autosomal recessively inherited
      cerebellar ataxia manifesting before 2 years of age.
    explanation: >-
      Supports recessive inheritance for the SCAR33 presentation.
pathophysiology:
- name: Minor spliceosome dysfunction from RNU12 variants
  description: >-
    Biallelic RNU12 variants disrupt the U12 small nuclear RNA, a core RNA
    component of the minor spliceosome. This compromises minor spliceosome
    stability and function and impairs normal processing of U12-type introns.
  genes:
  - preferred_term: RNU12
    term:
      id: hgnc:19380
      label: RNU12
  biological_processes:
  - preferred_term: U12-type intron splicing
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DECREASED
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNU12 encodes a small nuclear RNA that is a component of the minor
      spliceosome and is essential for minor intron splicing.
    explanation: >-
      Establishes that the disease gene encodes a core minor spliceosome RNA
      required for U12-type intron splicing.
  downstream:
  - target: U12-type intron retention and transcriptome dysregulation
- name: U12-type intron retention and transcriptome dysregulation
  description: >-
    Loss of normal minor spliceosome activity causes selective disruption of
    U12-type intron splicing with downstream transcriptome-wide dysregulation in
    minor intron-containing genes. Tissue-specific sensitivity to this shared
    splicing lesion likely determines whether the dominant presentation is
    cranio-cutaneous malformation or cerebellar neurodegeneration.
  biological_processes:
  - preferred_term: U12-type intron splicing
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DECREASED
  evidence:
  - reference: PMID:27863452
    reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reverse transcriptase PCR demonstrated minor intron retention in all of 9
      randomly selected RNAs from this group, and RNAseq showed splicing
      disruption specific to all U12-type introns detected in blood monocytes
      from affected individuals.
    explanation: >-
      Demonstrates selective U12-type intron retention in the ataxia
      presentation.
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whole transcriptome sequencing analysis of lymphoblastoid cells identified
      120 differentially expressed genes, and differential alternative splicing
      analysis indicated there was an enrichment of alternative splicing events
      in the patient.
    explanation: >-
      Extends the same splicing-dysregulation mechanism to the CDAGS
      presentation.
phenotypes:
- category: Craniofacial
  name: Craniosynostosis
  subtype: CDAGS
  description: >-
    Premature fusion of cranial sutures is a defining craniofacial feature of
    the CDAGS presentation within the RNU12 disease spectrum.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDAGS Syndrome is a rare congenital disorder characterized by
      Craniosynostosis, Delayed closure of the fontanelles, cranial defects,
      clavicular hypoplasia, Anal and Genitourinary malformations, and Skin
      manifestations.
    explanation: >-
      Directly supports craniosynostosis as part of the CDAGS subtype.
- category: Neurologic
  name: Early-onset cerebellar ataxia
  subtype: SCAR33
  description: >-
    Progressive or congenital cerebellar dysfunction with early motor
    impairment is the defining neurologic manifestation of the SCAR33 subtype.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:27863452
    reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WGS revealed a point mutation in noncoding RNA RNU12 that was associated
      with early onset cerebellar ataxia.
    explanation: >-
      Directly supports the defining ataxia phenotype of the SCAR33 subtype.
- category: Craniofacial
  name: Delayed closure of the anterior fontanelle
  subtype: CDAGS
  description: >-
    Delayed closure of the cranial fontanelles is one of the defining craniofacial
    features of CDAGS syndrome, reflecting aberrant skull ossification in RNU12-related
    minor spliceopathy.
  phenotype_term:
    preferred_term: Delayed closure of the anterior fontanelle
    term:
      id: HP:0001476
      label: Delayed closure of the anterior fontanelle
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDAGS Syndrome is a rare congenital disorder characterized by
      Craniosynostosis, Delayed closure of the fontanelles, cranial defects,
      clavicular hypoplasia, Anal and Genitourinary malformations, and Skin
      manifestations.
    explanation: >-
      Directly supports delayed fontanelle closure as part of the CDAGS acronym
      and clinical presentation.
- category: Musculoskeletal
  name: Clavicular hypoplasia
  subtype: CDAGS
  description: >-
    Underdevelopment of the clavicles is a defining skeletal feature of CDAGS
    syndrome, comprising the clavicular hypoplasia component of the acronym.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the clavicles
    term:
      id: HP:0006710
      label: Aplasia/Hypoplasia of the clavicles
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDAGS Syndrome is a rare congenital disorder characterized by
      Craniosynostosis, Delayed closure of the fontanelles, cranial defects,
      clavicular hypoplasia, Anal and Genitourinary malformations, and Skin
      manifestations.
    explanation: >-
      Directly supports clavicular hypoplasia as a defining feature of the CDAGS
      clinical presentation.
- category: Gastrointestinal
  name: Anal malformation
  subtype: CDAGS
  description: >-
    Anorectal malformations are a defining feature of CDAGS syndrome reflecting
    RNU12 involvement in anal patterning during development.
  phenotype_term:
    preferred_term: Abnormality of the anus
    term:
      id: HP:0004378
      label: Abnormality of the anus
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings provide evidence of the involvement of RNU12 in
      craniosynostosis, anal and genitourinary patterning, and cutaneous disease.
    explanation: >-
      Directly implicates RNU12 in anal patterning, supporting anal malformation
      as part of the CDAGS spectrum.
- category: Genitourinary
  name: Genitourinary malformation
  subtype: CDAGS
  description: >-
    Genitourinary anomalies are a defining feature of CDAGS syndrome reflecting
    RNU12 involvement in urogenital development.
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDAGS Syndrome is a rare congenital disorder characterized by
      Craniosynostosis, Delayed closure of the fontanelles, cranial defects,
      clavicular hypoplasia, Anal and Genitourinary malformations, and Skin
      manifestations.
    explanation: >-
      Directly supports genitourinary malformations as part of the CDAGS
      acronym and clinical spectrum.
- category: Skin
  name: Porokeratosis
  subtype: CDAGS
  description: >-
    Cutaneous manifestations including porokeratosis are a defining feature of
    CDAGS syndrome, comprising the skin component of the acronym.
  phenotype_term:
    preferred_term: Porokeratosis
    term:
      id: HP:0000951
      label: Abnormality of the skin
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings provide evidence of the involvement of RNU12 in
      craniosynostosis, anal and genitourinary patterning, and cutaneous disease.
    explanation: >-
      Supports cutaneous disease as part of CDAGS; porokeratosis is the specific
      skin manifestation named in the syndrome.
diagnosis:
- name: Molecular genetic testing for RNU12
  description: >-
    Diagnosis is confirmed by identification of biallelic pathogenic variants in
    RNU12. Whole exome sequencing or whole genome sequencing with Sanger
    confirmation of identified variants establishes the diagnosis in both CDAGS
    and SCAR33 presentations.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole exome and Sanger sequencing to identify the underlying
      molecular cause in five patients with CDAGS syndrome from four distinct
      families.
    explanation: >-
      Establishes whole exome sequencing with Sanger confirmation as the
      diagnostic approach for the CDAGS presentation.
  - reference: PMID:27863452
    reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole genome sequencing (WGS) was analyzed in a large consanguineous
      family in which members displayed autosomal recessively inherited
      cerebellar ataxia manifesting before 2 years of age.
    explanation: >-
      Establishes whole genome sequencing as the diagnostic approach for the
      SCAR33 presentation.
notes: >-
  This entry operationalizes MONDO NTR  # 9963 ("RNU12 - related minor
  spliceopathy disorder") as a local mechanism-defined umbrella disease. The
  broader umbrella is not yet available as a stable MONDO term in the local
  ontology snapshot, so no `disease_term` mapping is asserted here. The current
  Gene2Phenotype triage row only names RNU12-related CDAGS syndrome
  (MONDO:0011287), but the MONDO request and the literature support a broader
  RNU12 disease spectrum spanning CDAGS syndrome and SCAR33 through shared
  minor spliceosome dysfunction affecting U12-type intron splicing.
📚

References & Deep Research

Deep Research

1
Manual Pubmed Review ▸
RNU12-related Minor Spliceopathy Manual Deep-Research Note
n/a 2 citations 2026-04-19T00:45:00Z

RNU12-related Minor Spliceopathy Manual Deep-Research Note

Scope

  • Parent curation frame: local mechanism-defined umbrella disease for RNU12-related minor spliceopathy
  • MONDO status: umbrella concept tracked as MONDO NTR #9963, not yet a stable local MONDO term
  • Reported clinical presentations currently within scope:
  • MONDO:0011287 craniosynostosis-anal anomalies-porokeratosis syndrome (CDAGS)
  • MONDO:0859360 spinocerebellar ataxia, autosomal recessive 33 (SCAR33)
  • Shared molecular mechanism in scope:
  • biallelic RNU12 variation
  • minor spliceosome dysfunction
  • impaired U12-type intron splicing / minor intron retention

Primary Sources Used

  • PMID:34085356
  • Defines the CDAGS presentation and establishes biallelic RNU12 variants with transcriptome/splicing abnormalities in lymphoblastoid cells.
  • PMID:27863452
  • Defines the SCAR33 presentation and demonstrates selective disruption of U12-type intron splicing with minor intron retention in affected individuals.

Core Curation Decisions

Disease framing

  • The two disease papers support a broader shared-disorder frame rather than two fully unrelated single-presentation entries, because both presentations are caused by biallelic RNU12 disruption and converge on defective minor spliceosome function.
  • The YAML therefore uses a mechanism-defined umbrella root with explicit has_subtypes entries for CDAGS and SCAR33.

Initial phenotype scope

  • This first-pass PR intentionally models one high-signal anchor phenotype per subtype:
  • CDAGS -> craniosynostosis
  • SCAR33 -> early-onset cerebellar ataxia
  • The purpose of this minimal phenotype set is to establish the umbrella entry and subtype foreign-key structure without over-claiming frequency or phenotype completeness from only two primary abstracts.

Additional subtype features identified but deferred

  • CDAGS features explicitly named in PMID:34085356 and suitable for later phenotype expansion:
  • delayed closure of the fontanelles
  • cranial defects
  • clavicular hypoplasia
  • anal malformations
  • genitourinary malformations
  • skin manifestations including porokeratosis
  • SCAR33 features named in the disease report / summary framing and suitable for later phenotype expansion:
  • delayed motor development
  • hypotonia
  • tremor
  • nystagmus
  • dysarthria
  • cerebellar hypoplasia or degeneration

Evidence-Type Decision

  • The transcriptome / alternative splicing result from PMID:34085356 comes from lymphoblastoid cells and should be treated as IN_VITRO, not HUMAN_CLINICAL, even though the variants were discovered in human families.

Ontology Anchors Used

  • Disease / subtype terms:
  • MONDO:0011287 craniosynostosis-anal anomalies-porokeratosis syndrome
  • MONDO:0859360 spinocerebellar ataxia, autosomal recessive 33
  • Gene:
  • hgnc:19380 RNU12
  • Biological process:
  • GO:0000398 mRNA splicing, via spliceosome
  • Phenotypes:
  • HP:0001363 Craniosynostosis
  • HP:0001251 Ataxia, rendered with preferred term Cerebellar ataxia because the local HPO snapshot does not provide the reviewer-suggested HP:0002070 label for this concept.

Follow-up Work Deferred Beyond This PR

  • Expand subtype phenotype coverage using exact abstract-backed evidence items for additional CDAGS and SCAR33 manifestations.
  • Revisit whether a more specific GO term for minor/U12 spliceosome function is available and preferable to GO:0000398.
  • Add phenotype-targeted downstream links if the entry is expanded into a denser connected pathograph.