PRPF19-related neurodevelopmental disorder

Mendelian MONDO:1040005 Pathograph 14 Show in embeddings browser Genetic Disorder Neurodevelopmental Disorder

PRPF19-related neurodevelopmental disorder is a spliceosomopathy caused by heterozygous de novo variants in PRPF19, which encodes the U-box E3 ubiquitin ligase that is a core subunit of the Prp19 (NineTeen, NTC) complex required for catalytic activation and stabilization of the spliceosome. The disorder was defined in a series of six individuals carrying missense variants (mostly in the C-terminal WD40 beta-propeller), a frameshift, or a 400 kb duplication spanning the gene. Speech and language delay and motor delay were present in every individual old enough to assess, autism was diagnosed in four, and intellectual disability and hypotonia each occurred in three; the individual with the duplication had macrocephaly and tall stature, and the frameshift was found in a fetus with multiple congenital malformations. Functional data are limited: the frameshift abolishes binding to the NTC core partner CDC5L, and knockdown of the Drosophila ortholog reduces brain cell proliferation, disrupts mushroom body development, changes exon usage in several hundred genes and impairs social behaviour, which patient missense variants rescue only partly.

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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous variants, all de novo in the reported series; no familial transmission has been reported.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"We describe 3 NDDs caused by de novo heterozygous variants in U2AF2, PRPF19, and RBFOX1"
Heterozygous de novo variants, consistent with dominant inheritance.
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Discussions and Knowledge Gaps

1
How do the PRPF19 WD40 missense variants cause disease, given that they largely rescue the fly knockdown, and do PRPF19's ubiquitin ligase and DNA damage response roles, rather than splicing alone, contribute to the phenotype?
KNOWLEDGE GAP prpf19_missense_mechanism_and_non_splicing_roles
Attached to
pathophysiology#Germline PRPF19 Variant Disrupting the Prp19 Complex Subunit pathophysiology#Altered Exon Usage in Neural Transcripts
The disorder rests on six individuals from one report. Only the frameshift has a demonstrated molecular defect (loss of CDC5L binding); the missense variants are predicted to destabilize the WD40 propeller but were not tested for complex assembly, and in the fly they rescue lethality and brain structure while failing to restore social behaviour, which suggests a subtler or tissue-specific defect. All splicing evidence comes from ortholog knockdown, the shared U2AF2 effectors Iswi and Rbfox1 do not rescue the Prp19 phenotype, and no patient-derived cells have been profiled. PRPF19 also forms complexes in the DNA damage response, transcription elongation, mRNA export and protein degradation, and the authors leave their contribution open. The duplication carrier raises a separate dosage-gain question.
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT BACKGROUND In vitro / ex vivo
"In addition to the essential role in splicing, PRPF19 could form different complexes that are implicated in the DNA damage response, transcription elongation, mRNA export, and protein degradation"
The authors' own statement of the untested non-splicing roles.
PMID:20595234 SUPPORT INDIRECT In vitro / ex vivo
"the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains"
The ligase activity is itself used within the spliceosome, so a ubiquitination defect and a splicing defect need not be separable.
⚙

Pathophysiology

6
Germline PRPF19 Variant Disrupting the Prp19 Complex Subunit
A heterozygous de novo PRPF19 variant alters PRPF19, the U-box E3 ubiquitin ligase that forms the core of the Prp19 (NTC) complex with CDC5L and BCAS2 and assembles the other NTC-associated proteins through its C-terminal WD40 domain. Missense variants cluster in the WD40 beta-propeller and are predicted from structural modelling to destabilize propeller folding; the frameshift p.(His273Thrfs*37) truncates the WD40 domain. The ubiquitin ligase activity is bound here as the protein's own molecular function; no study has measured the effect of a patient variant on it.
PRPF19 hgnc:17896 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRPF19 (hgnc:17896). hgnc:17896 is a gene from the HUGO Gene Nomenclature Committee.
U-box E3 ubiquitin ligase activity GO:0061630 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves U-box E3 ubiquitin ligase activity, annotated with ubiquitin protein ligase activity (GO:0061630). GO:0061630 is a molecular function from the Gene Ontology.
Prp19 complex GO:0000974 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Prp19 complex (GO:0000974). GO:0000974 is a cellular component from the Gene Ontology.
Downstream
Impaired Prp19 Complex Assembly Loss or destabilization of the WD40 domain prevents PRPF19 from assembling with its NTC partners.
Show evidence (4 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"By GeneMatcher, we identified 5 more patients with heterozygous de novo PRPF19 variants"
Establishes heterozygous de novo PRPF19 variants as the disease trigger.
PMID:37962958 SUPPORT DIRECT Human clinical
"Variants in U2AF2 and RBFOX1 clustered predominantly in RNA recognition motifs, while a majority of PRPF19 variants were in the WD40 domain."
Locates most disease variants in the WD40 domain.
PMID:37962958 SUPPORT INDIRECT Computational
"are expected to destabilize the beta-propeller folding and in turn impair association with NTC-associated proteins"
Structural modelling predicts, without measurement, that the missense substitutions destabilize the WD40 propeller.
+ 1 more reference
Impaired Prp19 Complex Assembly
The truncating PRPF19 allele cannot bind CDC5L and so cannot form the Prp19 complex that drives spliceosome activation. For the missense alleles an assembly defect is predicted from modelling but was not demonstrated, and in the fly they largely replaced the endogenous protein.
Prp19 complex GO:0000974 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Prp19 complex (GO:0000974). GO:0000974 is a cellular component from the Gene Ontology.
Downstream
Altered Exon Usage in Neural Transcripts Reduced Prp19 complex function, modelled by knockdown of the fly ortholog, changes exon usage in a subset of neural transcripts.
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT In vitro / ex vivo
"The frameshift variant truncated the WD40 domain, leading to a complete loss of hPrp19 complex formation with CDC5L, which highly suggested that its canonical splicing function may have been lost."
Co-immunoprecipitation of the truncated protein in HEK293T cells.
PMID:37962958 SUPPORT DIRECT BACKGROUND In vitro / ex vivo
"The Prp19 complex, also known as NTC, has PRPF19 as one of the core subunits (i.e., PRPF19, CDC5L, and BCAS2) assembling the other Prp19 complex–associated proteins via C-terminal WD40 domains"
Background on the complex the WD40 domain assembles, restating prior biochemical and structural work.
Altered Exon Usage in Neural Transcripts
Pan-neural knockdown of Drosophila Prp19 changes exon usage in several hundred genes in larval brain, including increased inclusion of exons in Iswi, Brm, RpS19a and Rbfox1, rather than abolishing splicing. The evidence is from ortholog knockdown only; no splicing assay of a patient PRPF19 variant or of patient-derived cells has been reported, and restoring Iswi or Rbfox1 did not rescue the Prp19 knockdown brain phenotype, so the disease-relevant splicing targets are unknown. Knockdown models loss of function, while most patient variants are WD40 missense changes whose effect on PRPF19 dosage or activity is not known.
mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mRNA splicing, via spliceosome (GO:0000398). GO:0000398 is a biological process from the Gene Ontology.
Downstream
Reduced Neural Precursor Proliferation and Mushroom Body Development
Show evidence (2 references)
PMID:37962958 SUPPORT INDIRECT Model organism
"Prp19 RNAi (77% knockdown efficiency) led to 1,090 diffUEs in 727 unique genes"
Differential exon usage in fly larval brain after Prp19 knockdown.
PMID:37962958 SUPPORT INDIRECT Model organism
"However, Iswi and Rbfox1 failed to rescue the mushroom defects in Prp19-knockdown flies"
The candidate splicing effectors shared with U2AF2 do not explain the Prp19 phenotype, so its relevant targets remain unidentified.
Reduced Neural Precursor Proliferation and Mushroom Body Development
Pan-neural knockdown of fly Prp19 reduces larval brain cell proliferation, shrinks both lobes of the mushroom body, causes larval hypoactivity and is lethal before eclosion. Wild-type human PRPF19 and the two tested missense variants rescue lethality and the mushroom body defect, with p.(Gly404Ser) rescuing proliferation less completely, while the truncated p.(His273Thrfs*37) protein rescues neither. Both missense variants fail to restore normal social spacing in adult flies.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology.
Animal models
Drosophila neural Prp19 knockdown Fruit fly partially recapitulates Knockdown reduces brain cell proliferation and mushroom body size and is lethal; patient missense variants rescue lethality and structure but not social behaviour.
Downstream
Motor Delay
Autism
Intellectual Disability
Show evidence (3 references)
PMID:37962958 SUPPORT INDIRECT Model organism
"Similar to the phenotype caused by U2af50 knockdown, both the vertical and horizontal lobes of the MB exhibited remarkable area reduction in Prp19 RNAi larvae"
Mushroom body structural defect after neural knockdown.
PMID:37962958 SUPPORT INDIRECT Model organism
"In the fly rescue study, the truncated form failed to reinstate normal MB patterning."
The truncating allele behaves as a complete loss of function in vivo.
PMID:37962958 SUPPORT INDIRECT Model organism
"Moreover, compared with PRPF19WT and PPRF19Leu499Phe, which fully rescued the proliferation deficit, PRPF19Gly404Ser had reduced rescuing of larval brain proliferation"
One missense variant is a partial loss-of-function allele for proliferation.
PRPF19 Whole-Gene Duplication
A de novo 400 kb duplication spanning PRPF19 increases gene dosage. In the fly, overexpression of wild-type human PRPF19 increases brain cell proliferation, which the authors relate to the macrocephaly and tall stature of the individual carrying the duplication. The duplication spans other genes, so attribution of the phenotype to PRPF19 is not certain. This node is not declared conformant to the spliceosome module's variant node, which describes reduced dosage or altered sequence.
Downstream
Increased Neural Precursor Proliferation
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"a 400 kb duplication spanning PRPF19 (P3)"
The duplication carrier in the cohort.
Increased Neural Precursor Proliferation
Elevated proliferation of brain mitotic cells with increased PRPF19 dosage, shown in the fly overexpression model.
neural precursor cell proliferation GO:0061351 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology.
Downstream
Macrocephaly
Show evidence (1 reference)
PMID:37962958 SUPPORT INDIRECT Model organism
"The whole gene duplication resulted in elevated proliferation in brain mitotic neurons, which correlated with an NDD phenotype with macrocephaly and tall stature in participant P3."
The authors connect the fly overexpression result to the duplication carrier's phenotype.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PRPF19-related neurodevelopmental disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Head and Neck 1
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"consistent with the phenotype observed in participant P3, who has an increased HC (97%; Z = 1.95) and a tall stature"
Single individual; head circumference at the 97th centile (Z = 1.95), which the authors describe as macrocephaly.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Moreover, hypotonia was present in 3 individuals (P1, P2, and P4)."
Three of six individuals.
Nervous System 4
Delayed Speech and Language Development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Individuals P1–P5 all have speech/language and motor delays"
Five of six individuals, the sixth being a fetus; small series.
Motor Delay VERY_FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Individuals P1–P5 all have speech/language and motor delays"
Five of six individuals; small series.
Autism FREQUENT HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"individuals P1–P4 have a formal diagnosis of autism"
Four of six individuals.
Intellectual Disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Three individuals (P1, P4, and P5) had ID and 1 was normal (P3)."
Three of four assessed individuals.
Growth 1
Tall Stature HP:0000098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall stature (HP:0000098). HP:0000098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"consistent with the phenotype observed in participant P3, who has an increased HC (97%; Z = 1.95) and a tall stature"
Single individual.
🧬

Genetic Associations

1
PRPF19
Gene: PRPF19 hgnc:17896 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRPF19 (hgnc:17896). hgnc:17896 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants."
Defining series for the gene-disease association.
PMID:37962958 SUPPORT DIRECT Human clinical
"and missense (Z = 3.89) variants according to the gnomAD population database"
Missense constraint in gnomAD; the same sentence reports loss-of-function intolerance (pLI = 1), which sits inside a bracketed span the validator strips.
PMID:26663487 SUPPORT INDIRECT Model organism
"SNEV-knockout results in early embryonic lethality"
The gene is essential in the mouse.
Variants (2)
p.(Gly404Ser)
c.1210G>A, a de novo missense variant in the WD40 beta-propeller. In the fly it rescues lethality and the mushroom body defect but only partly rescues brain proliferation and does not restore normal social spacing.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"In 1 previously negative clinical exome, we identified a de novo variant, c.1210G>A, p.(Gly404Ser), in PRPF19"
Index case.
p.(His273Thrfs*37)
c.816delT, a frameshift truncating the WD40 domain, found in a fetus with multiple congenital malformations. It abolishes binding to CDC5L and fails to rescue the fly knockdown, behaving as a complete loss of function.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Model organism
"corroborating the fact that the variant c.816delT, p.(His273Thrfs*37) is indeed a complete LoF allele"
Loss of function shown by failed rescue in the fly and loss of CDC5L binding.
🐁

Animal Models

1
Drosophila neural Prp19 knockdown
Pan-neural knockdown of the fly PRPF19 ortholog with two independent RNAi lines, and rescue by wild-type or patient-variant human PRPF19.
Species
Fruit fly
Genotype
elav-Gal4 driven Prp19 RNAi, with or without UAS-PRPF19 WT, Gly404Ser, Leu499Phe or His273Thrfs*37
Publication
PMID:37962958
Pathograph links
Reduced Neural Precursor Proliferation and Mushroom Body Development partially recapitulates fidelity: moderate observes: tissue Knockdown reduces brain cell proliferation and mushroom body size and is lethal; patient missense variants rescue lethality and structure but not social behaviour.
Limitations: RNAi knockdown (77% reduction) models reduced dosage, which corresponds to the truncating allele but not directly to the heterozygous missense variants; the mushroom body has no direct human counterpart, and locomotor and social readouts are analogies to the human phenotypes.
Show evidence (1 reference)
PMID:37962958 SUPPORT Model organism
"Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19."
Summary of the fly model results.
{ }

Source YAML

click to show 
name: PRPF19-related neurodevelopmental disorder
creation_date: "2026-10-28T05:10:00Z"
category: Mendelian
description: >-
  PRPF19-related neurodevelopmental disorder is a spliceosomopathy caused by
  heterozygous de novo variants in PRPF19, which encodes the U-box E3 ubiquitin
  ligase that is a core subunit of the Prp19 (NineTeen, NTC) complex required
  for catalytic activation and stabilization of the spliceosome. The
  disorder was defined in a series of six individuals carrying missense
  variants (mostly in the C-terminal WD40 beta-propeller), a frameshift, or a
  400 kb duplication spanning the gene. Speech and language delay and motor
  delay were present in every individual old enough to assess, autism was
  diagnosed in four, and intellectual disability and hypotonia each occurred in
  three; the individual with the duplication had macrocephaly and tall
  stature, and the frameshift was found in a fetus with multiple congenital
  malformations. Functional data are limited: the frameshift abolishes binding
  to the NTC core partner CDC5L, and knockdown of the Drosophila ortholog
  reduces brain cell proliferation, disrupts mushroom body development, changes
  exon usage in several hundred genes and impairs social behaviour, which
  patient missense variants rescue only partly.
disease_term:
  preferred_term: PRPF19-related neurodevelopmental disorder
  term:
    id: MONDO:1040005
    label: PRPF19-related neurodevelopmental disorder
synonyms:
- PRPF19-related neurodevelopmental disorder
parents:
- Genetic Disorder
- Neurodevelopmental Disorder
pathophysiology:
- name: Germline PRPF19 Variant Disrupting the Prp19 Complex Subunit
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    A heterozygous de novo PRPF19 variant alters PRPF19, the U-box E3 ubiquitin
    ligase that forms the core of the Prp19 (NTC) complex with CDC5L and BCAS2
    and assembles the other NTC-associated proteins through its C-terminal WD40
    domain. Missense variants cluster in the WD40 beta-propeller and are
    predicted from structural modelling to destabilize propeller folding; the
    frameshift p.(His273Thrfs*37) truncates the WD40 domain. The ubiquitin
    ligase activity is bound here as the protein's own molecular function; no
    study has measured the effect of a patient variant on it.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PRPF19
    term:
      id: hgnc:17896
      label: PRPF19
  molecular_functions:
  - preferred_term: U-box E3 ubiquitin ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
  cellular_components:
  - preferred_term: Prp19 complex
    term:
      id: GO:0000974
      label: Prp19 complex
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "By GeneMatcher, we identified 5 more patients with heterozygous de novo PRPF19 variants"
    explanation: Establishes heterozygous de novo PRPF19 variants as the disease trigger.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in U2AF2 and RBFOX1 clustered predominantly in RNA recognition motifs, while a majority of PRPF19 variants were in the WD40 domain."
    explanation: Locates most disease variants in the WD40 domain.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "are expected to destabilize the beta-propeller folding and in turn impair association with NTC-associated proteins"
    explanation: >-
      Structural modelling predicts, without measurement, that the missense
      substitutions destabilize the WD40 propeller.
  - reference: PMID:15660529
    reference_title: "Interaction of U-box E3 ligase SNEV with PSMB4, the beta7 subunit of the 20 S proteasome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "SNEV has E3 ligase activity in vitro, when tested with Ubc3 (cdc34) as E2 enzyme, and that the ubiquitin transfer is dependent on the U-box"
    explanation: >-
      SNEV is a synonym of PRPF19; the sentence restates earlier biochemical
      work showing U-box-dependent E3 ubiquitin ligase activity.
  downstream:
  - target: Impaired Prp19 Complex Assembly
    description: >-
      Loss or destabilization of the WD40 domain prevents PRPF19 from
      assembling with its NTC partners.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "cells transfected with PRPF19His273Thrfs*37 showed a complete loss of binding with CDC5L"
      explanation: Shown for the frameshift allele only.
- name: Impaired Prp19 Complex Assembly
  description: >-
    The truncating PRPF19 allele cannot bind CDC5L and so cannot form the Prp19
    complex that drives spliceosome activation. For the missense alleles an
    assembly defect is predicted from modelling but was not demonstrated, and
    in the fly they largely replaced the endogenous protein.
  role: central_effector
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Prp19 complex
    term:
      id: GO:0000974
      label: Prp19 complex
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The frameshift variant truncated the WD40 domain, leading to a complete loss of hPrp19 complex formation with CDC5L, which highly suggested that its canonical splicing function may have been lost."
    explanation: Co-immunoprecipitation of the truncated protein in HEK293T cells.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The Prp19 complex, also known as NTC, has PRPF19 as one of the core subunits (i.e., PRPF19, CDC5L, and BCAS2) assembling the other Prp19 complex–associated proteins via C-terminal WD40 domains"
    explanation: >-
      Background on the complex the WD40 domain assembles, restating prior
      biochemical and structural work.
  downstream:
  - target: Altered Exon Usage in Neural Transcripts
    description: >-
      Reduced Prp19 complex function, modelled by knockdown of the fly
      ortholog, changes exon usage in a subset of neural transcripts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Prp19 RNAi (77% knockdown efficiency) led to 1,090 diffUEs in 727 unique genes"
      explanation: >-
        Knockdown reduces dosage, which models the truncating allele rather
        than the missense alleles.
- name: Altered Exon Usage in Neural Transcripts
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  description: >-
    Pan-neural knockdown of Drosophila Prp19 changes exon usage in several
    hundred genes in larval brain, including increased inclusion of exons in
    Iswi, Brm, RpS19a and Rbfox1, rather than abolishing splicing. The
    evidence is from ortholog knockdown only; no splicing assay of a patient
    PRPF19 variant or of patient-derived cells has been reported, and restoring
    Iswi or Rbfox1 did not rescue the Prp19 knockdown brain phenotype, so the
    disease-relevant splicing targets are unknown. Knockdown models loss of
    function, while most patient variants are WD40 missense changes whose
    effect on PRPF19 dosage or activity is not known.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Prp19 RNAi (77% knockdown efficiency) led to 1,090 diffUEs in 727 unique genes"
    explanation: Differential exon usage in fly larval brain after Prp19 knockdown.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "However, Iswi and Rbfox1 failed to rescue the mushroom defects in Prp19-knockdown flies"
    explanation: >-
      The candidate splicing effectors shared with U2AF2 do not explain the
      Prp19 phenotype, so its relevant targets remain unidentified.
  downstream:
  - target: Reduced Neural Precursor Proliferation and Mushroom Body Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "As expected, all pan-neural Prp19–knockdown flies died before eclosion (Supplemental Figure 5A) and resulted in a generalized reduction in brain cell proliferation"
      explanation: >-
        The same knockdown that alters exon usage reduces brain cell
        proliferation; which splicing changes cause it is not shown.
- name: Reduced Neural Precursor Proliferation and Mushroom Body Development
  description: >-
    Pan-neural knockdown of fly Prp19 reduces larval brain cell proliferation,
    shrinks both lobes of the mushroom body, causes larval hypoactivity and is
    lethal before eclosion. Wild-type human PRPF19 and the two tested missense
    variants rescue lethality and the mushroom body defect, with
    p.(Gly404Ser) rescuing proliferation less completely, while the truncated
    p.(His273Thrfs*37) protein rescues neither. Both missense variants fail
    to restore normal social spacing in adult flies.
  role: downstream_consequence
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Similar to the phenotype caused by U2af50 knockdown, both the vertical and horizontal lobes of the MB exhibited remarkable area reduction in Prp19 RNAi larvae"
    explanation: Mushroom body structural defect after neural knockdown.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In the fly rescue study, the truncated form failed to reinstate normal MB patterning."
    explanation: The truncating allele behaves as a complete loss of function in vivo.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, compared with PRPF19WT and PPRF19Leu499Phe, which fully rescued the proliferation deficit, PRPF19Gly404Ser had reduced rescuing of larval brain proliferation"
    explanation: One missense variant is a partial loss-of-function allele for proliferation.
  downstream:
  - target: Motor Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We assessed the total crawling length, distance, and speed and found that RNAi larvae had overt hypoactivity"
      explanation: >-
        Larval locomotor deficit, tested because patients with missense
        variants have motor deficits; the correspondence is by analogy.
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "This result indicated that, although the 2 PRPF19 missense variants drastically extended the lifespan of Prp19-knockdown flies, they did not completely rescue their social behaviors."
      explanation: >-
        Social-spacing deficit in flies expressing patient missense variants,
        the experimental counterpart of the autism diagnoses.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of U2af50 or Prp19 may lead to compromised MB function in neural processing and in the regulation of higher-order social behavior, mimicking the patients with impaired intellectual functions."
      explanation: Stated by the authors as a possibility.
- name: PRPF19 Whole-Gene Duplication
  description: >-
    A de novo 400 kb duplication spanning PRPF19 increases gene dosage. In the
    fly, overexpression of wild-type human PRPF19 increases brain cell
    proliferation, which the authors relate to the macrocephaly and tall
    stature of the individual carrying the duplication. The duplication spans
    other genes, so attribution of the phenotype to PRPF19 is not certain.
    This node is not declared conformant to the spliceosome module's variant
    node, which describes reduced dosage or altered sequence.
  role: trigger
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 400 kb duplication spanning PRPF19 (P3)"
    explanation: The duplication carrier in the cohort.
  downstream:
  - target: Increased Neural Precursor Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Of note, overexpression of PRPF19WT significantly increased cell proliferation"
      explanation: Overexpression in the fly brain models increased dosage.
- name: Increased Neural Precursor Proliferation
  description: >-
    Elevated proliferation of brain mitotic cells with increased PRPF19 dosage,
    shown in the fly overexpression model.
  role: downstream_consequence
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The whole gene duplication resulted in elevated proliferation in brain mitotic neurons, which correlated with an NDD phenotype with macrocephaly and tall stature in participant P3."
    explanation: >-
      The authors connect the fly overexpression result to the duplication
      carrier's phenotype.
  downstream:
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The whole gene duplication resulted in elevated proliferation in brain mitotic neurons, which correlated with an NDD phenotype with macrocephaly and tall stature in participant P3."
      explanation: A correlation in one individual, linked to the fly result by the authors.
phenotypes:
- category: Neurodevelopmental
  name: Delayed Speech and Language Development
  description: >-
    Speech and language delay in all five postnatally assessed individuals
    (the sixth was a fetus).
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals P1–P5 all have speech/language and motor delays"
    explanation: Five of six individuals, the sixth being a fetus; small series.
- category: Neurodevelopmental
  name: Motor Delay
  description: Motor delay in all five postnatally assessed individuals.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals P1–P5 all have speech/language and motor delays"
    explanation: Five of six individuals; small series.
- category: Behavioral
  name: Autism
  description: A formal diagnosis of autism in four of six individuals.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  frequency: FREQUENT
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals P1–P4 have a formal diagnosis of autism"
    explanation: Four of six individuals.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability in three of the four individuals assessed; one
    individual had normal intellect and one was too young to assess.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three individuals (P1, P4, and P5) had ID and 1 was normal (P3)."
    explanation: Three of four assessed individuals.
- category: Neurological
  name: Hypotonia
  description: Hypotonia in three of six individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, hypotonia was present in 3 individuals (P1, P2, and P4)."
    explanation: Three of six individuals.
- category: Growth
  name: Macrocephaly
  description: >-
    Increased head circumference in the individual with the whole-gene
    duplication; not reported with the point variants.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "consistent with the phenotype observed in participant P3, who has an increased HC (97%; Z = 1.95) and a tall stature"
    explanation: >-
      Single individual; head circumference at the 97th centile (Z = 1.95),
      which the authors describe as macrocephaly.
- category: Growth
  name: Tall Stature
  description: Tall stature in the individual with the whole-gene duplication.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "consistent with the phenotype observed in participant P3, who has an increased HC (97%; Z = 1.95) and a tall stature"
    explanation: Single individual.
genetic:
- name: PRPF19
  gene_term:
    preferred_term: PRPF19
    term:
      id: hgnc:17896
      label: PRPF19
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Pre-mRNA processing factor 19 (also known as SNEV or PSO4), a U-box E3
    ubiquitin ligase and core subunit of the Prp19/NTC complex. The defining
    series reports six individuals with de novo variants: missense
    p.(Gly404Ser), p.(Leu499Phe), p.(Arg422Cys) and p.(Arg128Gln), the
    frameshift p.(His273Thrfs*37), and a 400 kb duplication spanning the gene.
    The paper's results and discussion assign the frameshift to different
    participant labels (P6 and P4), so this entry does not tie variants to
    participant labels beyond what is quoted. PRPF19 is constrained against
    both loss-of-function (pLI = 1) and missense variation in gnomAD. Mouse
    knockout is early embryonic lethal. No ClinGen gene-disease validity
    record for PRPF19 is present in the local structured-source cache, so
    gene_disease_validity is left absent.
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants."
    explanation: Defining series for the gene-disease association.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "and missense (Z = 3.89) variants according to the gnomAD population database"
    explanation: >-
      Missense constraint in gnomAD; the same sentence reports loss-of-function
      intolerance (pLI = 1), which sits inside a bracketed span the validator
      strips.
  - reference: PMID:26663487
    reference_title: "SNEV(Prp19/PSO4) deficiency increases PUVA-induced senescence in mouse skin."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "SNEV-knockout results in early embryonic lethality"
    explanation: The gene is essential in the mouse.
  variants:
  - name: p.(Gly404Ser)
    description: >-
      c.1210G>A, a de novo missense variant in the WD40 beta-propeller. In the
      fly it rescues lethality and the mushroom body defect but only partly
      rescues brain proliferation and does not restore normal social spacing.
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 1 previously negative clinical exome, we identified a de novo variant, c.1210G>A, p.(Gly404Ser), in PRPF19"
      explanation: Index case.
  - name: p.(His273Thrfs*37)
    description: >-
      c.816delT, a frameshift truncating the WD40 domain, found in a fetus with
      multiple congenital malformations. It abolishes binding to CDC5L and
      fails to rescue the fly knockdown, behaving as a complete loss of
      function.
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "corroborating the fact that the variant c.816delT, p.(His273Thrfs*37) is indeed a complete LoF allele"
      explanation: Loss of function shown by failed rescue in the fly and loss of CDC5L binding.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous variants, all de novo in the reported series; no familial
    transmission has been reported.
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe 3 NDDs caused by de novo heterozygous variants in U2AF2, PRPF19, and RBFOX1"
    explanation: Heterozygous de novo variants, consistent with dominant inheritance.
animal_models:
- name: Drosophila neural Prp19 knockdown
  species: Fruit fly
  genotype: elav-Gal4 driven Prp19 RNAi, with or without UAS-PRPF19 WT, Gly404Ser, Leu499Phe or His273Thrfs*37
  publication: PMID:37962958
  description: >-
    Pan-neural knockdown of the fly PRPF19 ortholog with two independent RNAi
    lines, and rescue by wild-type or patient-variant human PRPF19.
  modeled_mechanisms:
  - target: Reduced Neural Precursor Proliferation and Mushroom Body Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Knockdown reduces brain cell proliferation and mushroom body size and is
      lethal; patient missense variants rescue lethality and structure but not
      social behaviour.
    limitations: >-
      RNAi knockdown (77% reduction) models reduced dosage, which corresponds
      to the truncating allele but not directly to the heterozygous missense
      variants; the mushroom body has no direct human counterpart, and
      locomotor and social readouts are analogies to the human phenotypes.
    evidence:
    - reference: PMID:37962958
      reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19."
      explanation: Summary of the fly model results.
discussions:
- discussion_id: prpf19_missense_mechanism_and_non_splicing_roles
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Germline PRPF19 Variant Disrupting the Prp19 Complex Subunit
  - pathophysiology#Altered Exon Usage in Neural Transcripts
  prompt: >-
    How do the PRPF19 WD40 missense variants cause disease, given that they
    largely rescue the fly knockdown, and do PRPF19's ubiquitin ligase and DNA
    damage response roles, rather than splicing alone, contribute to the
    phenotype?
  rationale: >-
    The disorder rests on six individuals from one report. Only the frameshift
    has a demonstrated molecular defect (loss of CDC5L binding); the missense
    variants are predicted to destabilize the WD40 propeller but were not
    tested for complex assembly, and in the fly they rescue lethality and brain
    structure while failing to restore social behaviour, which suggests a
    subtler or tissue-specific defect. All splicing evidence comes from
    ortholog knockdown, the shared U2AF2 effectors Iswi and Rbfox1 do not
    rescue the Prp19 phenotype, and no patient-derived cells have been
    profiled. PRPF19 also forms complexes in the DNA damage response,
    transcription elongation, mRNA export and protein degradation, and the
    authors leave their contribution open. The duplication carrier raises a
    separate dosage-gain question.
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "In addition to the essential role in splicing, PRPF19 could form different complexes that are implicated in the DNA damage response, transcription elongation, mRNA export, and protein degradation"
    explanation: The authors' own statement of the untested non-splicing roles.
  - reference: PMID:20595234
    reference_title: "The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains"
    explanation: >-
      The ligase activity is itself used within the spliceosome, so a
      ubiquitination defect and a splicing defect need not be separable.