Spliceosomopathies (germline spliceosome component disorders)

name: Spliceosomopathies
display_name: Spliceosomopathies (germline spliceosome component disorders)
creation_date: "2026-10-25T00:00:00Z"
description: >-
  Disorders caused by germline variants in genes encoding RNA or protein
  components of the major or minor spliceosome. Each member mis-splices a
  sensitive subset of transcripts, and the disease falls on the cell types
  least able to tolerate that: cranial neural crest in the mandibulofacial and
  acrofacial dysostoses, photoreceptors and retinal pigment epithelium in
  PRPF31 retinopathy, the developing brain in the snRNA-gene
  neurodevelopmental disorders, and multiple developing tissues in the minor
  spliceosome disorders.
grouping_basis:
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared mechanism: every member conforms to the
  spliceosome_component_dysfunction module, in which a component defect causes
  mis-splicing of a sensitive transcript subset and failure of
  splicing-sensitive cells. The members stay separate Disease entries because they
  differ in the gene and spliceosome subunit affected, whether the major or
  minor spliceosome is hit, inheritance (dominant haploinsufficiency, dominant
  variants clustered in one snRNA element, or biallelic loss), and the tissue
  that fails. Defects that mis-splice only their own transcript, somatic
  splicing-factor mutations in myeloid neoplasms, and snRNP assembly defects
  such as SMN deficiency are outside this grouping.
membership_criteria:
- description: >-
    A disorder belongs to the spliceosomopathies if it has a pathophysiology
    node conforming to the spliceosome_component_dysfunction module.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: spliceosome_component_dysfunction
    description: >-
      Anchored to the module stem rather than one node, because members
      conform at the trigger, the mis-splicing node and, for some, the P53 or
      cell-failure nodes.
members:
- member: RNU5B-1 Related Neurodevelopmental Disorder With Seizures And Joint Laxity
  member_type: DISEASE
  display_name: RNU5B-1-related neurodevelopmental disorder
  differentiating_mechanisms:
  - description: >-
      Dominant, mostly de novo variants in U5 snRNA loop I; no shared splicing
      signature across variants, and the mutant may act by altered function or
      be degraded by snRNA quality control.
    gene:
      preferred_term: RNU5B-1
      term:
        id: hgnc:10212
        label: RNU5B-1
- member: ReNU Syndrome
  member_type: DISEASE
  display_name: ReNU syndrome
  differentiating_mechanisms:
  - description: >-
      Dominant de novo variants in the U4 snRNA T-loop and stem III, with a
      shared 5' splice-site signature whose strength tracks severity.
    gene:
      preferred_term: RNU4-2
      term:
        id: hgnc:10193
        label: RNU4-2
- member: RNU12-related minor spliceopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic variants in U12 snRNA of the minor spliceosome, causing U12-type
      intron retention.
    gene:
      preferred_term: RNU12
      term:
        id: hgnc:19380
        label: RNU12
- member: RNU4ATAC Spectrum Disorder
  member_type: GROUPING
  display_name: RNU4ATAC spectrum disorder
  differentiating_mechanisms:
  - description: >-
      Biallelic RNU4ATAC variants impair U4atac snRNA of the minor spliceosome.
      Variants that destabilize U4atac in its 5' stem-loop give severe
      minor-spliceosome failure with microcephalic primordial dwarfism (MOPD
      I). Genotypes with variants mostly outside the 5' stem-loop give the
      milder phenotypes: Roifman syndrome, with a prominent immunodeficiency,
      and Lowry-Wood syndrome, a multiple epiphyseal dysplasia with
      microcephaly and nystagmus.
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
- member: PRPF31-Related Retinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Dominant PRPF31 haploinsufficiency impairs tri-snRNP assembly; disease is
      confined to the retina, with incomplete penetrance set by the wild-type
      allele's expression.
    gene:
      preferred_term: PRPF31
      term:
        id: hgnc:15446
        label: PRPF31
- member: PRPF8-Related Retinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Dominant PRPF8 missense variants in the C-terminal region weaken
      repression of the Brr2 helicase, altering 5' splice-site selection in
      ciliary and retinal transcripts; retina-restricted, with frequent cystoid
      macular edema.
    gene:
      preferred_term: PRPF8
      term:
        id: hgnc:17340
        label: PRPF8
- member: SNRNP200-Related Dominant Retinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Dominant missense variants in the Brr2 helicase itself impair U4/U6
      unwinding and 5' splice-site recognition while still assembling into
      spliceosomes; retina-restricted and milder on average than PRPF-gene
      retinopathy.
    gene:
      preferred_term: SNRNP200
      term:
        id: hgnc:30859
        label: SNRNP200
- member: Mandibulofacial dysostosis with microcephaly
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      EFTUD2 haploinsufficiency in the U5 snRNP; neural crest loss with Mdm2
      exon skipping and P53 activation.
    gene:
      preferred_term: EFTUD2
      term:
        id: hgnc:30858
        label: EFTUD2
- member: Nager Acrofacial Dysostosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SF3B4 haploinsufficiency in the U2 snRNP SF3b complex, with increased exon
      skipping and cranial neural crest loss plus preaxial limb defects.
    gene:
      preferred_term: SF3B4
      term:
        id: hgnc:10771
        label: SF3B4
- member: Cerebrocostomandibular Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SNRPB variants that increase inclusion of its own premature-stop exon, so
      the defect starts as autoregulatory mis-splicing of a core Sm protein;
      rib and jaw malformations.
    gene:
      preferred_term: SNRPB
      term:
        id: hgnc:11153
        label: SNRPB
- member: Burn-McKeown Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reduced TXNL4A dosage, usually from a recurrent promoter deletion,
      impairing U4/U6.U5 tri-snRNP assembly.
    gene:
      preferred_term: TXNL4A
      term:
        id: hgnc:30551
        label: TXNL4A
- member: SNIP1-Related Neurodevelopmental Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A biallelic Amish founder missense variant in SNIP1, a component of the
      RES complex recruited to the activated spliceosome, causing widespread
      mis-splicing with infantile-onset drug-resistant epilepsy and a
      characteristic craniofacial gestalt.
    gene:
      preferred_term: SNIP1
      term:
        id: hgnc:30587
        label: SNIP1
- member: Neuromuscular Disease And Ocular Or Auditory Anomalies With Or Without Seizures
  member_type: DISEASE
  display_name: DHX16-related neuromuscular oculoauditory syndrome
  differentiating_mechanisms:
  - description: >-
      De novo missense variants in DHX16, the DEAH-box ATPase that activates
      the spliceosome before the first catalytic step, causing intron
      retention and selective neuromuscular, ocular and auditory failure.
    gene:
      preferred_term: DHX16
      term:
        id: hgnc:2739
        label: DHX16
- member: Neurodevelopmental Disorder with Hypotonia, Feeding Difficulties, Facial Dysmorphism, and Brain Abnormalities
  member_type: DISEASE
  display_name: WBP4-related neurodevelopmental disorder
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of WBP4, a B-complex protein that restrains SNRNP200,
      causing transcriptome-wide mis-splicing of neurodevelopmental and
      musculoskeletal genes.
    gene:
      preferred_term: WBP4
      term:
        id: hgnc:12739
        label: WBP4
- member: Intellectual Developmental Disorder, Autosomal Dominant 72
  member_type: DISEASE
  display_name: SRRM2-related neurodevelopmental disorder
  differentiating_mechanisms:
  - description: >-
      Heterozygous loss of SRRM2, a catalytic-centre splicing factor and
      nuclear speckle scaffold, dysregulating alternative splicing with a mild
      neurodevelopmental phenotype.
    gene:
      preferred_term: SRRM2
      term:
        id: hgnc:16639
        label: SRRM2
- member: U2AF2-related neurodevelopmental disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mostly de novo variants in the RNA recognition motifs of U2AF2, the
      U2AF65 subunit that binds the polypyrimidine tract at 3' splice sites,
      altering splicing of neurodevelopmental RNA-binding protein transcripts.
    gene:
      preferred_term: U2AF2
      term:
        id: hgnc:23156
        label: U2AF2
- member: PRPF19-related neurodevelopmental disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      De novo variants in PRPF19, the E3 ubiquitin ligase core of the Prp19
      complex that activates the spliceosome; mis-splicing is shown so far
      only in fly ortholog knockdown.
    gene:
      preferred_term: PRPF19
      term:
        id: hgnc:17896
        label: PRPF19
- member: CWC27-Related Retinitis Pigmentosa With or Without Skeletal Anomalies
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of CWC27, a catalytically inactive cyclophilin of the
      activated spliceosome, causing retinal intron retention and
      photoreceptor degeneration, with skeletal and developmental features in
      more severe alleles.
    gene:
      preferred_term: CWC27
      term:
        id: hgnc:10664
        label: CWC27
- member: Hypotrichosis 11
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Dominant variants in SNRPE, an Sm core protein of the U snRNPs,
      restricted to hair; the founding study found no major splicing defect in
      patient lymphocytes or minigene assays.
    gene:
      preferred_term: SNRPE
      term:
        id: hgnc:11161
        label: SNRPE
- member: LSM7-related Leukodystrophy and Cerebellar Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic LSM7 variants that misassemble both the spliceosomal LSm2-8
      ring and the mRNA-decay LSm1-7 ring; which defect causes oligodendrocyte
      loss is unresolved.
    gene:
      preferred_term: LSM7
      term:
        id: hgnc:20470
        label: LSM7
- member: RNU4-2-Related Autosomal Recessive Neurodevelopmental Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic RNU4-2 variants outside the ReNU critical region, in stem II,
      the Sm site and the terminal stem loop, lowering U4 snRNA levels; no
      splicing defect has been detected in patient blood.
    gene:
      preferred_term: RNU4-2
      term:
        id: hgnc:10193
        label: RNU4-2
- member: U4 and U6 snRNA Gene-Related Retinitis Pigmentosa
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Dominant variants in the U4/U6 three-way junction of RNU4-2 and RNU6
      genes that alter di-snRNP factor binding and delay tri-snRNP assembly;
      retina-restricted, with no consistent splicing change in patient
      leukocytes.
    gene:
      preferred_term: RNU4-2
      term:
        id: hgnc:10193
        label: RNU4-2
notes: >-
  SF3B2 is one of several genes behind craniofacial microsomia, and that
  entry's SF3B2 node also carries FOXI3, GBX2 and SHROOM3, so craniofacial
  microsomia is not a member. Dominant RNU2-2 disease (developmental and
  epileptic encephalopathy 119) is a subtype of
  Genetic_Developmental_and_Epileptic_Encephalopathy rather than a Disease
  entry, so it cannot be a member; see projects/SPLICE_VARIANTS.md.