🔗

Mappings

MONDO

MONDO:0033717 congenital cerebellar ataxia due to RNU12 mutation Not Yet Curated

MONDO:0033717 is the Orphanet-derived (ORPHA:512260) term for the RNU12 early-onset cerebellar ataxia presentation, which this entry curates as the SCAR33 subtype alongside its OMIM-derived term MONDO:0859360. narrowMatch rather than exactMatch because this entry is the broader RNU12 minor spliceopathy umbrella that also covers CDAGS syndrome.

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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.

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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 MONDO:0033717

MONDO MONDO:0033717

Early-onset neurologic presentation characterized by autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age, with differential expression of minor intron-containing RNAs including genes associated with cerebellar neurodegeneration. Orphanet names the same disease congenital cerebellar ataxia due to RNU12 mutation (ORPHA:512260; MONDO:0033717) and describes infantile delayed motor milestones, hypotonia, intention tremor, nystagmus, dysarthria, and mixed cerebellar hypoplasia and vermian degeneration on imaging. It differs from the CDAGS subtype in being a purely neurologic presentation caused by a homozygous RNU12 point mutation rather than compound heterozygous alleles.

Show evidence (4 references)

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.

ORPHA:512260 SUPPORT Other

"MONDO:0033717 | Exact"

Orphanet maps its congenital cerebellar ataxia due to RNU12 mutation record exactly to MONDO:0033717.

ORPHA:512260 SUPPORT Other

"OMIM:620208 | Exact"

The same Orphanet record maps exactly to OMIM:620208, the OMIM entry from which MONDO:0859360 (SCAR33) is derived, so the two MONDO terms name one disease.

+ 1 more reference

⚙

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, by altering the precursor U12 snRNA 3' extension or disrupting the secondary structure or Sm protein binding site of the RNU12 snRNA. This compromises minor spliceosome stability and function and impairs normal processing of U12-type introns.

RNU12 hgnc:19380

U12-type intron splicing GO:0000398 ↓ DECREASED

Downstream

U12-type intron retention and transcriptome dysregulation Impaired U12 snRNA function in the minor spliceosome leads directly to retention of U12-type introns and downstream transcriptomic dysregulation.

Show evidence (2 references)

PMID:34085356 SUPPORT Human clinical

"All five patients shared the same rare mutation NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide within the precursor U12 snRNA 3' extension. Each of them also carried a rare variant on the other allele that either disrupts the secondary structure or the Sm binding site of..."

Demonstrates that pathogenic RNU12 variants alter the precursor 3' extension or disrupt the secondary structure or Sm protein binding site of the U12 snRNA.

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 GO:0000398 ↓ DECREASED

Downstream

Craniosynostosis Impaired minor spliceosome function from biallelic RNU12 variants leads to craniosynostosis in the CDAGS syndrome presentation.

Early-onset cerebellar ataxia U12-type intron retention and differential expression of minor intron-containing RNAs, including transcripts for genes associated with cerebellar neurodegeneration, lead to early-onset cerebellar ataxia in the SCAR33 presentation.

Delayed closure of the anterior fontanelle Impaired minor spliceosome function from biallelic RNU12 variants leads to delayed closure of the fontanelles in CDAGS syndrome.

Calvarial skull defect Impaired minor spliceosome function from biallelic RNU12 variants leads to cranial defects in CDAGS syndrome.

Clavicular hypoplasia Impaired minor spliceosome function from biallelic RNU12 variants leads to clavicular hypoplasia in CDAGS syndrome.

Anal malformation Impaired minor spliceosome function from biallelic RNU12 variants leads to anal patterning defects and malformations in CDAGS syndrome.

Genitourinary malformation Impaired minor spliceosome function from biallelic RNU12 variants leads to genitourinary patterning defects and malformations in CDAGS syndrome.

Porokeratosis Impaired minor spliceosome function from biallelic RNU12 variants leads to cutaneous manifestations including porokeratosis in CDAGS syndrome.

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 / ex vivo

"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

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Phenotypes

14

Digestive 1

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.

Eye 1

Nystagmus OCCASIONAL HP:0000639

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0000639 | Nystagmus | Occasional (29-5%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

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 3

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.

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.

Calvarial skull defect HP:0001362

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 cranial defects as part of the CDAGS clinical presentation.

Integument 1

Porokeratosis HP:0200044

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 2

Axial hypotonia FREQUENT HP:0008936

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0008936 | Axial hypotonia | Frequent (79-30%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

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 5

Early-onset cerebellar 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.

Intention tremor FREQUENT HP:0002080

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0002080 | Intention tremor | Frequent (79-30%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

Dysarthria FREQUENT HP:0001260

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0001260 | Dysarthria | Frequent (79-30%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

Cerebellar vermis atrophy FREQUENT HP:0006855

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0006855 | Cerebellar vermis atrophy | Frequent (79-30%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

Delayed gross motor development FREQUENT HP:0002194

Show evidence (1 reference)

ORPHA:512260 SUPPORT Other

"HP:0002194 | Delayed gross motor development | Frequent (79-30%)"

Orphanet phenotype annotation for congenital cerebellar ataxia due to RNU12 mutation (the SCAR33 subtype).

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Genetic Associations

1

RNU12 (Causal biallelic noncoding snRNA variants)

Gene: RNU12 hgnc:19380

Show evidence (3 references)

PMID:34085356 SUPPORT Human clinical

"Whole exome sequencing revealed biallelic rare variants that disrupt highly conserved nucleotides within the RNU12 gene."

Demonstrates causal biallelic RNU12 variants in patients with CDAGS syndrome.

PMID:34085356 SUPPORT Human clinical

"All five patients shared the same rare mutation NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide within the precursor U12 snRNA 3' extension. Each of them also carried a rare variant on the other allele that either disrupts the secondary structure or the Sm binding site of..."

Details the recurrent precursor 3'-extension variant and trans alleles disrupting U12 snRNA secondary structure or Sm binding site in CDAGS syndrome.

PMID:27863452 SUPPORT Human clinical

"WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia."

Demonstrates a causal homozygous point mutation in RNU12 in early-onset autosomal recessive cerebellar ataxia (SCAR33).

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Diagnosis

1

Molecular genetic testing for RNU12

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.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:34085356 SUPPORT Human clinical

"We performed whole exome and Sanger sequencing to identify the underlying molecular cause in five patients with CDAGS syndrome from four distinct families."

Establishes whole exome sequencing with Sanger confirmation as the diagnostic approach for the CDAGS presentation.

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."

Establishes whole genome sequencing as the diagnostic approach for the SCAR33 presentation.

{ }

Source YAML

click to show

name: RNU12-related minor spliceopathy
creation_date: "2026-04-16T00:00:00Z"
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.
disease_term:
  preferred_term: RNU12-related minor spliceopathy disorder
  term:
    id: MONDO:1060223
    label: RNU12-related minor spliceopathy disorder
synonyms:
- RNU12-related minor spliceopathy disorder
- RNU12-related spliceopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0033717
      label: congenital cerebellar ataxia due to RNU12 mutation
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0033717 is the Orphanet-derived (ORPHA:512260) term for the
      RNU12 early-onset cerebellar ataxia presentation, which this entry
      curates as the SCAR33 subtype alongside its OMIM-derived term
      MONDO:0859360. narrowMatch rather than exactMatch because this entry is
      the broader RNU12 minor spliceopathy umbrella that also covers CDAGS
      syndrome.
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 characterized by autosomal recessively
    inherited cerebellar ataxia manifesting before 2 years of age, with
    differential expression of minor intron-containing RNAs including genes
    associated with cerebellar neurodegeneration. Orphanet names the same
    disease congenital cerebellar ataxia due to RNU12 mutation (ORPHA:512260;
    MONDO:0033717) and describes infantile delayed motor milestones,
    hypotonia, intention tremor, nystagmus, dysarthria, and mixed cerebellar
    hypoplasia and vermian degeneration on imaging. It differs from the CDAGS
    subtype in being a purely neurologic presentation caused by a homozygous
    RNU12 point mutation rather than compound heterozygous alleles.
  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.
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0033717 | Exact"
    explanation: >-
      Orphanet maps its congenital cerebellar ataxia due to RNU12 mutation
      record exactly to MONDO:0033717.
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:620208 | Exact"
    explanation: >-
      The same Orphanet record maps exactly to OMIM:620208, the OMIM entry from
      which MONDO:0859360 (SCAR33) is derived, so the two MONDO terms name one
      disease.
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare hereditary ataxia characterized by delayed motor milestones in
      early infancy, hypotonia, ataxic gait, intention tremor, nystagmus,
      dysarthric speech, and variable learning difficulties.
    explanation: >-
      Orphanet clinical definition of the RNU12 congenital cerebellar ataxia
      presentation.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0033717
        label: congenital cerebellar ataxia due to RNU12 mutation
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:512260
      mapping_justification: >-
        MONDO:0033717 is the Orphanet-derived term (ORPHA:512260) and
        MONDO:0859360 the OMIM-derived term (OMIM:620208) for the same disease.
        Orphanet lists both MONDO:0033717 and OMIM:620208 as exact
        cross-references of ORPHA:512260, and both rest on the single
        consanguineous family reported in PMID:27863452.
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
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    Biallelic RNU12 variants disrupt the U12 small nuclear RNA, a core RNA
    component of the minor spliceosome, by altering the precursor U12 snRNA 3'
    extension or disrupting the secondary structure or Sm protein binding site
    of the RNU12 snRNA. 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: >-
      All five patients shared the same rare mutation NC_000022.10:g.43011402C>T,
      which alters a highly conserved nucleotide within the precursor U12 snRNA
      3' extension. Each of them also carried a rare variant on the other allele
      that either disrupts the secondary structure or the Sm binding site of the
      RNU12 snRNA.
    explanation: >-
      Demonstrates that pathogenic RNU12 variants alter the precursor 3'
      extension or disrupt the secondary structure or Sm protein binding site of
      the U12 snRNA.
  - 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
    description: >-
      Impaired U12 snRNA function in the minor spliceosome leads directly to
      retention of U12-type introns and downstream transcriptomic dysregulation.
    causal_link_type: DIRECT
    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 that RNU12 mutation causes widespread U12-type intron
        retention across minor-intron-containing transcripts.
    - 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: >-
        Shows enrichment of alternative splicing events and transcriptomic
        dysregulation downstream of biallelic RNU12 variants in CDAGS syndrome.
- name: U12-type intron retention and transcriptome dysregulation
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  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.
  downstream:
  - target: Craniosynostosis
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      craniosynostosis in the CDAGS syndrome presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Links RNU12 minor spliceosome dysfunction to craniosynostosis in CDAGS
        syndrome.
  - target: Early-onset cerebellar ataxia
    description: >-
      U12-type intron retention and differential expression of minor
      intron-containing RNAs, including transcripts for genes associated with
      cerebellar neurodegeneration, lead to early-onset cerebellar ataxia in the
      SCAR33 presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27863452
      reference_title: Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Moreover, 144 minor intron-containing RNAs were differentially expressed,
        including transcripts for 3 genes previously associated with cerebellar
        neurodegeneration.
      explanation: >-
        Connects RNU12-mediated minor intron splicing disruption and
        differential expression of cerebellar neurodegeneration-associated
        transcripts to early-onset cerebellar ataxia.
  - target: Delayed closure of the anterior fontanelle
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      delayed closure of the fontanelles in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Connects RNU12-related CDAGS spliceopathy to delayed closure of the
        fontanelles.
  - target: Calvarial skull defect
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      cranial defects in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Connects RNU12-related CDAGS spliceopathy to cranial defects.
  - target: Clavicular hypoplasia
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      clavicular hypoplasia in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Connects RNU12-related CDAGS spliceopathy to clavicular hypoplasia.
  - target: Anal malformation
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      anal patterning defects and malformations in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Implicates RNU12 splicing dysfunction in anal patterning defects.
  - target: Genitourinary malformation
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      genitourinary patterning defects and malformations in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Implicates RNU12 splicing dysfunction in genitourinary patterning
        defects.
  - target: Porokeratosis
    description: >-
      Impaired minor spliceosome function from biallelic RNU12 variants leads to
      cutaneous manifestations including porokeratosis in CDAGS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Links RNU12 minor spliceosome dysfunction to the cutaneous manifestations
        of CDAGS syndrome.
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: Neurologic
  name: Intention tremor
  subtype: SCAR33
  frequency: FREQUENT
  description: >-
    Movement-provoked cerebellar tremor. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it frequent.
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002080 | Intention tremor | Frequent (79-30%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (the SCAR33 subtype).
- category: Neurologic
  name: Dysarthria
  subtype: SCAR33
  frequency: FREQUENT
  description: >-
    Cerebellar dysarthric speech. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it frequent.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (the SCAR33 subtype).
- category: Neurologic
  name: Cerebellar vermis atrophy
  subtype: SCAR33
  frequency: FREQUENT
  description: >-
    Thinning of the vermian folia on neuroimaging. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it frequent.
  phenotype_term:
    preferred_term: Cerebellar vermis atrophy
    term:
      id: HP:0006855
      label: Cerebellar vermis atrophy
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006855 | Cerebellar vermis atrophy | Frequent (79-30%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (the SCAR33 subtype).
- category: Neurologic
  name: Axial hypotonia
  subtype: SCAR33
  frequency: FREQUENT
  description: >-
    Reduced truncal tone in infancy. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it frequent.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008936 | Axial hypotonia | Frequent (79-30%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (the SCAR33 subtype).
- category: Neurologic
  name: Delayed gross motor development
  subtype: SCAR33
  frequency: FREQUENT
  description: >-
    Delayed motor milestones from early infancy. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it frequent.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002194 | Delayed gross motor development | Frequent (79-30%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (the SCAR33 subtype).
- category: Neurologic
  name: Nystagmus
  subtype: SCAR33
  frequency: OCCASIONAL
  description: >-
    Involuntary rhythmic eye movements. Reported in the RNU12 congenital cerebellar ataxia presentation;
    Orphanet grades it occasional.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:512260
    reference_title: Congenital cerebellar ataxia due to RNU12 mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Occasional (29-5%)"
    explanation: >-
      Orphanet phenotype annotation for congenital cerebellar ataxia due to
      RNU12 mutation (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 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: Craniofacial
  name: Calvarial skull defect
  subtype: CDAGS
  description: >-
    Cranial defects are a defining craniofacial manifestation of CDAGS syndrome
    in RNU12-related minor spliceopathy.
  phenotype_term:
    preferred_term: Calvarial skull defect
    term:
      id: HP:0001362
      label: Calvarial skull defect
  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 cranial defects as part of the CDAGS 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:0200044
      label: Porokeratosis
  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.
genetic:
- name: RNU12
  association: Causal biallelic noncoding snRNA variants
  gene_term:
    preferred_term: RNU12
    term:
      id: hgnc:19380
      label: RNU12
  notes: >-
    Biallelic pathogenic single-nucleotide variants in conserved elements of the
    noncoding U12 small nuclear RNA gene RNU12 cause both CDAGS syndrome and
    early-onset autosomal recessive cerebellar ataxia (SCAR33). In CDAGS
    syndrome, all five reported patients shared NC_000022.10:g.43011402C>T in
    the precursor U12 snRNA 3' extension in compound heterozygosity with a
    second rare variant disrupting either the secondary structure or the Sm
    binding site of the RNU12 snRNA, whereas SCAR33 was caused by a homozygous
    point mutation in noncoding RNA RNU12.
  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: >-
      Demonstrates causal biallelic RNU12 variants in patients with CDAGS
      syndrome.
  - reference: PMID:34085356
    reference_title: Biallelic variants in RNU12 cause CDAGS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five patients shared the same rare mutation NC_000022.10:g.43011402C>T,
      which alters a highly conserved nucleotide within the precursor U12 snRNA
      3' extension. Each of them also carried a rare variant on the other allele
      that either disrupts the secondary structure or the Sm binding site of the
      RNU12 snRNA.
    explanation: >-
      Details the recurrent precursor 3'-extension variant and trans alleles
      disrupting U12 snRNA secondary structure or Sm binding site in CDAGS
      syndrome.
  - 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: >-
      Demonstrates a causal homozygous point mutation in RNU12 in early-onset
      autosomal recessive cerebellar ataxia (SCAR33).
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: NCIT:C15709
      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 mechanism-defined umbrella disease. That request has since been minted as MONDO:1060223 (\"RNU12-related minor spliceopathy disorder\"), which is now anchored as the top-level `disease_term` for this entry. The current Gene2Phenotype triage row only names RNU12-related CDAGS syndrome (MONDO:0011287), but the broader MONDO umbrella and the literature support a wider RNU12 disease spectrum spanning CDAGS syndrome and SCAR33 through shared minor spliceosome dysfunction affecting U12-type intron splicing."

📚

References & Deep Research

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)

Review: RNU12-related minor spliceopathy (Changes required) · 2026-05-30T05:00:00Z · View source

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3449 Issue state: CLOSED Issue created: 2026-05-30T05:00:00Z Issue updated: 2026-05-30T15:51:04Z Issue closed: 2026-05-30T15:51:04Z Review decision: Changes required Labels: curation, medium_effort, review ## Completed curation review - Disease: **RNU12-related minor spliceopathy** - Entry: `kb/disorders/RNU12-related_Minor_Spliceopathy.yaml` - Selection basis: #57 of the least-recently edited Mendelian entries - Review decision: **Changes required** - Validation stance: assumes schema/term/reference validation passes; this is a biological and clinical-content review. ## Findings 1. **The entry is currently too sparse.** It has two phenotypes and two pathophysiology nodes, with no genetics evidence details, diagnosis, treatments, or management. RNU12-related disease needs enough content for CDAGS and SCAR33 to be independently interpretable. 2. **Subtype-specific phenotypes are missing.** CDAGS includes craniosynostosis, clavicular hypoplasia, anal anomalies, genitourinary anomalies, and skin eruption; SCAR33 is early-onset cerebellar ataxia. The YAML only has craniosynostosis and early-onset cerebellar ataxia. 3. **Inheritance and genetics need variant detail.** Autosomal recessive is present, but the entry should specify RNU12 snRNA/minor spliceosome pathogenic variants and subtype-associated alleles where known. 4. **Diagnosis and management are absent.** Add molecular testing, neurologic evaluation/MRI for SCAR33, craniofacial/anorectal/GU/skeletal evaluation for CDAGS, and supportive/surgical/rehabilitative management. 5. **Mechanism should connect U12-type intron retention to tissue phenotypes.** Minor spliceosome dysfunction is correct but should be linked to transcriptome dysregulation and developmental/neurodegenerative consequences by subtype. ## Research-artifact cross-check Matching artifact: `research/RNU12-related_Minor_Spliceopathy-deep-research-manual.md`. The YAML under-consumes the artifact's subtype framing and clinical details. ## Content-completeness summary - **Phenotypes:** insufficient for both CDAGS and SCAR33. - **Subtype/lumping:** subtypes exist but need phenotype/diagnosis/mechanism mapping. - **Pathophysiology:** high-level mechanism present; downstream specificity missing. - **Management/diagnosis:** absent. - **References:** add primary CDAGS/SCAR33 RNU12 references if updating YAML. ## Sources used - RNU12/CDAGS review context: https://pmc.ncbi.nlm.nih.gov/articles/PMC6262367/ - RNU12/SCAR33 report, PMID:29100092: https://pubmed.ncbi.nlm.nih.gov/29100092/ No YAML files or `references_cache/*.md` files were edited.

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.

RNU12-related minor spliceopathy

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OpenScientist Report

Mappings

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Diagnosis

Source YAML

References & Deep Research

Deep Research

RNU12-related Minor Spliceopathy Manual Deep-Research Note

Scope

Primary Sources Used

Core Curation Decisions

Disease framing

Initial phenotype scope

Additional subtype features identified but deferred

Evidence-Type Decision

Ontology Anchors Used

Follow-up Work Deferred Beyond This PR