U2AF2-related neurodevelopmental disorder

Mendelian MONDO:0957810 Pathograph 12 Show in embeddings browser Genetic Disorder Neurodevelopmental Disorder

U2AF2-related neurodevelopmental disorder is a spliceosomopathy caused by heterozygous, almost always de novo, variants in U2AF2, which encodes the large subunit of the U2 auxiliary factor (U2AF65) that recognizes the polypyrimidine tract at major-class 3' splice sites during the earliest step of spliceosome assembly. Disease-associated missense variants cluster in the two RNA recognition motifs, with recurrent hotspots at Arg149 and Arg150. The core phenotype is global developmental, speech and motor delay with mild-to-severe intellectual disability, hypotonia, seizures (often febrile), brain anomalies of which a thin or hypoplastic corpus callosum is the most frequent, autistic features and behavioural problems, and a shared facial gestalt. Functional studies show the recurrent variants weaken binding to polypyrimidine-tract RNA, reduce splicing of a reporter, behave as partial loss-of-function alleles in Drosophila, and shorten neurites in human stem-cell-derived neurons.

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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous variants, nearly all arising de novo; no familial transmission has been reported in the cited cohort.
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, all of which are involved in the pre-mRNA splicing machinery."
Heterozygous de novo variants, consistent with dominant inheritance.
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Discussions and Knowledge Gaps

1
Do the recurrent RRM missense variants act purely as partial loss of function equivalent to reduced U2AF2 dosage, and which human neural transcripts mis-spliced by them account for the brain phenotype?
KNOWLEDGE GAP u2af2_dosage_versus_altered_function
Attached to
pathophysiology#Germline U2AF2 RNA Recognition Motif Variant pathophysiology#Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts
Fly rescue experiments classify the recurrent variants as partial loss of function, and a whole-gene deletion produces an overlapping phenotype, but the missense proteins are expressed at normal levels and missense variants cluster at RNA-contacting residues, which leaves open a dominant or substrate-specific component. The splicing targets identified so far come from fly brain knockdown and from non-neural human cell lines; no transcriptome of patient-derived neurons carrying the variants has identified the disease-relevant human splicing events. The facial, growth and cardiac features have no mechanistic node in this entry for the same reason.
Show evidence (1 reference)
PMID:42135263 SUPPORT INDIRECT Human clinical
"The patient's clinical features overlap substantially with those reported in individuals harboring heterozygous U2AF2 variants, supporting haploinsufficiency as a plausible disease mechanism."
Supports a dosage model, while the deletion's other genes make this indirect.
⚙

Pathophysiology

3
Germline U2AF2 RNA Recognition Motif Variant
A heterozygous de novo U2AF2 variant, usually a missense change in RNA recognition motif 1 or 2, alters the U2AF65 subunit that binds the polypyrimidine tract of 3' splice sites. The recurrent Arg149Trp, Arg150His and Arg150Cys substitutions lower the affinity of U2AF2 for a consensus polypyrimidine-tract RNA by roughly three- to five-fold by disrupting Arg146 contacts with the terminal nucleotide, without changing U2AF2 protein abundance or nuclear localization.
U2AF2 hgnc:23156 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves U2AF2 (hgnc:23156). hgnc:23156 is a gene from the HUGO Gene Nomenclature Committee.
polypyrimidine tract RNA binding at the 3' splice site GO:0030628 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased polypyrimidine tract RNA binding at the 3' splice site, annotated with pre-mRNA 3'-splice site binding (GO:0030628). GO:0030628 is a molecular function from the Gene Ontology.
Downstream
Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts Weakened polypyrimidine-tract recognition reduces splicing at U2AF2-sensitive 3' splice sites and shifts exon usage in a subset of transcripts.
Show evidence (5 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"Together, we identified 23 U2AF2 variants associated with an NDD, including 21 de novo and 7 recurrent variants, in the RRMs required for RNA recognition."
Places the disease-associated variants, mostly de novo, in the RNA recognition motifs of U2AF2.
PMID:37962958 SUPPORT DIRECT Human clinical
"The U2AF2 RRMs serve the major function of recognizing polypyrimidine (Py) tract signals marking 3′ splice sites"
States the molecular function the variant-bearing domains carry, which is the function bound on this node.
PMID:39388459 SUPPORT DIRECT In vitro / ex vivo
"Here, we demonstrated by fluorescence anisotropy RNA binding assays that recurrent missense mutants (Arg149Trp, Arg150His, or Arg150Cys) decreased the binding affinity of U2AF2 for a consensus splice site RNA."
Direct biochemical measurement of reduced polypyrimidine-tract binding by the three recurrent variants.
+ 2 more references
Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts
Reduced U2AF2 function changes exon usage in a subset of transcripts rather than abolishing splicing. In U2af50-deficient fly brain and in U2AF2-depleted human cell lines the affected set is enriched for transcripts encoding RNA-binding proteins, including Rbfox1 and other neurodevelopmental splicing regulators, and restoring Iswi, Rbfox1 or RpS19a partially rescues the fly brain phenotype. Which human neural transcripts carry the disease is not yet established.
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
Impaired Neurogenesis and Neurite Outgrowth Altered splicing of neural splicing regulators and other substrates impairs neural progenitor proliferation and neurite growth.
Show evidence (4 references)
PMID:37962958 SUPPORT DIRECT In vitro / ex vivo
"Indeed, we observed that coexpression of 8 of 18 mutant constructs and the pyPY minigene in HEK293T cells significantly reduced py splicing"
Patient variants reduce splicing at the weaker, uridine-poor polypyrimidine tract of the reporter.
PMID:37962958 SUPPORT INDIRECT Model organism
"Analysis of U2af50 RNAi RNA-Seq data with moderate knockdown efficiency (49%) revealed 234 diffUEs in 185 unique genes"
Partial knockdown of the fly ortholog changes exon usage in a limited set of genes, consistent with a sensitive subset rather than global failure.
PMID:39388459 SUPPORT INDIRECT Computational
"Reanalysis of publicly available RNaseq data confirmed that U2AF2 depletion altered splicing of transcripts encoding RNA binding proteins (RBPs)."
Reanalysis of ENCODE knockdown data in human cell lines identifies U2AF2-sensitive splicing of RNA-binding-protein transcripts.
+ 1 more reference
Impaired Neurogenesis and Neurite Outgrowth
Neurons differentiated from human pluripotent stem cells carrying the hyper-recurrent Arg149Trp or Arg150Cys variant have shorter neurites, and neural knockdown of the fly ortholog U2af50 reduces neural progenitor proliferation, shrinks the mushroom body, and produces heat-induced seizure-like paralysis and social deficits, none of which the patient variants fully rescue.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron projection development GO:0031175 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron projection development (GO:0031175). GO:0031175 is a biological process from the Gene Ontology.
Animal models
Drosophila neural U2af50 knockdown Fruit fly partially recapitulates Knockdown reduces brain progenitor proliferation and mushroom body size and produces seizure-like paralysis; patient variants rescue these only partly.
Downstream
Global Developmental Delay
Intellectual Disability
Seizures
Autistic Behavior
Thin Corpus Callosum
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT In vitro / ex vivo
"Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants."
Isogenic human neuron model of the two commonest variants.
PMID:37962958 SUPPORT INDIRECT Model organism
"These results strongly suggest that, while WT U2AF2 could largely replace U2af50 in flies, the 2 variants were partial LoF alleles."
Rescue experiments in neural U2af50-knockdown flies classify the recurrent variants as partial loss of function.
⬡

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 U2AF2-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

17
Cardiovascular 1
Congenital Heart Abnormality OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart abnormality, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"In 11 of 42 individuals (26%), heart abnormalities were reported."
Frequency in the cohort; lesion types not given in the text.
PMID:42135263 SUPPORT DIRECT Human clinical
"presenting with intellectual disability, epilepsy, corpus callosum hypoplasia, dysmorphic features, and congenital heart disease"
Congenital heart disease in a patient with a whole-gene deletion; the deletion spans other genes, so attribution to U2AF2 is not certain.
Eye 3
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Clinical photographs of 19 participants show several shared craniofacial features, including a prominent/broad forehead, a high anterior hairline, deep-set eyes, hypertelorism, short palpebral fissures"
Hypertelorism is among the shared facial features.
Deeply Set Eyes HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep-set eyes, annotated with Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Clinical photographs of 19 participants show several shared craniofacial features, including a prominent/broad forehead, a high anterior hairline, deep-set eyes"
Deep-set eyes are among the shared facial features.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34112922 SUPPORT DIRECT Human clinical
"intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum"
Single-case observation.
Head and Neck 2
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"5 individuals had microcephaly (head circumference [HC] ≤ –2 SD), 3 individuals had macrocephaly (HC ≥ +2 SD), and 4 individuals had obesity."
Microcephaly in 5 of the cohort, with macrocephaly in 3.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"a narrow nasal bridge with an upturned nose, thin upper lips, micrognathia, a wide mouth, wide-spaced teeth, and a short neck"
Micrognathia is among the shared facial features.
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
"Hypotonia was identified in 25 of 37 probands (68%)."
Frequency in the cohort.
Nervous System 9
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"All individuals except 2 (individuals 27 and 33, who died before 6 months of age) had developmental delay ranging from mild to severe, and most of them had global developmental delay involving speech and language, cognition, motor skills, and social behavior."
Cohort of 46 individuals.
PMID:34112922 SUPPORT DIRECT Human clinical
"The patient showed global developmental delay, intellectual disability, epilepsy, short stature, microcephaly, facial dysmorphism"
First clinically detailed case report (Arg149Trp).
Delayed Speech and Language Development 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 (2 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"These data reveal a neurodevelopmental phenotype associated with U2AF2 de novo missense variants, with core features of global developmental, speech, and motor delays"
Speech delay is named among the core features.
PMID:36747105 SUPPORT DIRECT Human clinical
"including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum"
Language delay in an independent case.
Intellectual Disability VERY_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
"ID was present in 30 of 34 (88%) of the individuals assessed, with a severity ranging from mild (n = 22) to severe (n = 8) ID."
Gives frequency (88%) and severity range.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Seizures occurred in 23 of 41 participants (56%), 15 of whom had febrile seizures (65%)."
Frequency of seizures and of the febrile subset.
Febrile Seizures FREQUENT Febrile seizure (within the age range of 3 months to 6 years) HP:0002373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Febrile seizure, annotated with Febrile seizure (within the age range of 3 months to 6 years) (HP:0002373). HP:0002373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Seizures occurred in 23 of 41 participants (56%), 15 of whom had febrile seizures (65%)."
15 of 41 participants (about 37%) had febrile seizures.
Thin Corpus Callosum OCCASIONAL HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37962958 SUPPORT DIRECT Human clinical
"Brain MRI was performed in 34 probands, and 14 (41%) had abnormal imaging findings, including delayed myelination, ventricle asymmetry, atrophy of the cerebral hemisphere, absent olfactory bulbs and tracts, dysmorphic inferior frontal gyri, and, the most prevalent finding, a thin or poorly..."
9 of 34 imaged individuals (about 26%) had a thin or poorly developed corpus callosum.
PMID:34112922 SUPPORT DIRECT Human clinical
"intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum"
Thin corpus callosum in the first case report.
Delayed CNS Myelination HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"had abnormal imaging findings, including delayed myelination, ventricle asymmetry, atrophy of the cerebral hemisphere"
Delayed myelination is among the reported MRI findings.
Autistic Behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"A formal diagnosis of ASD was made in 6 individuals, with 5 additional individuals having autistic features (11 of 39)"
11 of 39 individuals (28%).
Behavioral Abnormality FREQUENT Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral disturbance, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"with a total of 64% (25 of 39) of the participants identified as having behavioral issues"
Frequency of behavioural issues in the cohort.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37962958 SUPPORT DIRECT Human clinical
"Ten individuals had postnatal short stature (height ≤ –2 SD; 10 of 40), 5 individuals had microcephaly"
10 of 40 individuals (25%).
🧬

Genetic Associations

1
U2AF2
Gene: U2AF2 hgnc:23156 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is U2AF2 (hgnc:23156). hgnc:23156 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)"
Largest cohort establishing the gene-disease association.
PMID:34112922 SUPPORT DIRECT Human clinical
"Here, we report an individual with a de novo U2AF2 variant (c.445C>T, p.(Arg149Trp)) using trio-based whole-exome sequencing."
First clinically detailed de novo case.
PMID:37092751 SUPPORT DIRECT Human clinical
"Here, we report a patient with a de novo missense variant in U2AF2, the second case report of the same variant, and third case report overall."
Independent recurrence of the same variant.
Variants (2)
p.(Arg149Trp)
c.445C>T, the commonest recurrent missense variant, in RRM1. Reduces polypyrimidine-tract RNA binding and is a partial loss-of-function allele in Drosophila rescue assays.
Show evidence (2 references)
PMID:39388459 SUPPORT DIRECT BACKGROUND Human clinical
"Two U2AF2 residues harbor outstanding, recurrent mutations among different patients (Figure 1A): Arg149, which is changed to tryptophan in 85% of cases"
Recurrence of the Arg149Trp change among patients, cited as background in a biochemical study.
PMID:41090043 SUPPORT DIRECT Human clinical
"Recurrent U2AF2 c.445C>T variant in two cases with systemic dysmorphism, epilepsy, and neurodevelopmental regression"
Two further cases with the same variant.
c.603G>T (exon 6 skipping)
Presumed missense variant shown in patient lymphoblastoid cells to cause exon 6 skipping and an in-frame deletion (p.E163_E201del).
Show evidence (1 reference)
PMID:36747105 SUPPORT DIRECT In vitro / ex vivo
"the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del)"
RNA and protein analysis in patient-derived cells.
🐁

Animal Models

1
Drosophila neural U2af50 knockdown
Pan-neural, mushroom-body and motor-neuron knockdown of the fly U2AF2 ortholog, with rescue by wild-type or patient-variant human U2AF2.
Species
Fruit fly
Genotype
elav-Gal4 driven U2af50 RNAi, with or without UAS-U2AF2 WT, Arg149Trp or Arg150Cys
Publication
PMID:37962958
Pathograph links
Impaired Neurogenesis and Neurite Outgrowth partially recapitulates fidelity: moderate observes: tissue Knockdown reduces brain progenitor proliferation and mushroom body size and produces seizure-like paralysis; patient variants rescue these only partly.
Limitations: RNAi knockdown (about 49% reduction) models reduced dosage rather than the heterozygous missense lesion directly; the mushroom body has no direct human counterpart, and behaviour and seizure 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: U2AF2-related neurodevelopmental disorder
creation_date: "2026-10-28T12:00:00Z"
category: Mendelian
description: >-
  U2AF2-related neurodevelopmental disorder is a spliceosomopathy caused by
  heterozygous, almost always de novo, variants in U2AF2, which encodes the
  large subunit of the U2 auxiliary factor (U2AF65) that recognizes the
  polypyrimidine tract at major-class 3' splice sites during the earliest step
  of spliceosome assembly. Disease-associated missense variants cluster in the
  two RNA recognition motifs, with recurrent hotspots at Arg149 and Arg150.
  The core phenotype is global developmental, speech and motor delay with
  mild-to-severe intellectual disability, hypotonia, seizures (often febrile),
  brain anomalies of which a thin or hypoplastic corpus callosum is the most
  frequent, autistic features and behavioural problems, and a shared facial
  gestalt. Functional studies show the recurrent variants weaken binding to
  polypyrimidine-tract RNA, reduce splicing of a reporter, behave as partial
  loss-of-function alleles in Drosophila, and shorten neurites in human
  stem-cell-derived neurons.
disease_term:
  preferred_term: developmental delay, dysmorphic facies, and brain anomalies
  term:
    id: MONDO:0957810
    label: developmental delay, dysmorphic facies, and brain anomalies
synonyms:
- developmental delay, dysmorphic facies, and brain anomalies
- U2AF2-related neurodevelopmental disorder
- DEDDFAB
parents:
- Genetic Disorder
- Neurodevelopmental Disorder
pathophysiology:
- name: Germline U2AF2 RNA Recognition Motif Variant
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    A heterozygous de novo U2AF2 variant, usually a missense change in RNA
    recognition motif 1 or 2, alters the U2AF65 subunit that binds the
    polypyrimidine tract of 3' splice sites. The recurrent Arg149Trp,
    Arg150His and Arg150Cys substitutions lower the affinity of U2AF2 for a
    consensus polypyrimidine-tract RNA by roughly three- to five-fold by
    disrupting Arg146 contacts with the terminal nucleotide, without changing
    U2AF2 protein abundance or nuclear localization.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: U2AF2
    term:
      id: hgnc:23156
      label: U2AF2
  molecular_functions:
  - preferred_term: polypyrimidine tract RNA binding at the 3' splice site
    term:
      id: GO:0030628
      label: pre-mRNA 3'-splice site binding
    modifier: DECREASED
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, we identified 23 U2AF2 variants associated with an NDD, including 21 de novo and 7 recurrent variants, in the RRMs required for RNA recognition."
    explanation: >-
      Places the disease-associated variants, mostly de novo, in the RNA
      recognition motifs of U2AF2.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The U2AF2 RRMs serve the major function of recognizing polypyrimidine (Py) tract signals marking 3′ splice sites"
    explanation: >-
      States the molecular function the variant-bearing domains carry, which is
      the function bound on this node.
  - reference: PMID:39388459
    reference_title: "Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Here, we demonstrated by fluorescence anisotropy RNA binding assays that recurrent missense mutants (Arg149Trp, Arg150His, or Arg150Cys) decreased the binding affinity of U2AF2 for a consensus splice site RNA."
    explanation: >-
      Direct biochemical measurement of reduced polypyrimidine-tract binding by
      the three recurrent variants.
  - reference: PMID:39388459
    reference_title: "Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Crystal structures at 1.4 Å resolutions showed that Arg149Trp or Arg150His disrupted hydrogen bonds between U2AF2 and the terminal nucleotides of the RNA site."
    explanation: Structural basis of the weakened RNA binding.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The abundance of all mutant U2AF2 proteins was comparable to WT"
    explanation: >-
      The missense variants alter function rather than protein level, which is
      why the lesion is recorded as a change in RNA binding.
  downstream:
  - target: Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts
    description: >-
      Weakened polypyrimidine-tract recognition reduces splicing at
      U2AF2-sensitive 3' splice sites and shifts exon usage in a subset of
      transcripts.
    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: "Eight U2AF2 variants dysregulated splicing of a model substrate."
      explanation: >-
        Patient variants reduce splicing of a polypyrimidine-tract minigene
        reporter in HEK293T cells.
- name: Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  description: >-
    Reduced U2AF2 function changes exon usage in a subset of transcripts rather
    than abolishing splicing. In U2af50-deficient fly brain and in U2AF2-depleted
    human cell lines the affected set is enriched for transcripts encoding
    RNA-binding proteins, including Rbfox1 and other neurodevelopmental
    splicing regulators, and restoring Iswi, Rbfox1 or RpS19a partially rescues
    the fly brain phenotype. Which human neural transcripts carry the disease is
    not yet established.
  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: DIRECT
    evidence_source: IN_VITRO
    snippet: "Indeed, we observed that coexpression of 8 of 18 mutant constructs and the pyPY minigene in HEK293T cells significantly reduced py splicing"
    explanation: >-
      Patient variants reduce splicing at the weaker, uridine-poor
      polypyrimidine tract of the reporter.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of U2af50 RNAi RNA-Seq data with moderate knockdown efficiency (49%) revealed 234 diffUEs in 185 unique genes"
    explanation: >-
      Partial knockdown of the fly ortholog changes exon usage in a limited set
      of genes, consistent with a sensitive subset rather than global failure.
  - reference: PMID:39388459
    reference_title: "Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Reanalysis of publicly available RNaseq data confirmed that U2AF2 depletion altered splicing of transcripts encoding RNA binding proteins (RBPs)."
    explanation: >-
      Reanalysis of ENCODE knockdown data in human cell lines identifies
      U2AF2-sensitive splicing of RNA-binding-protein transcripts.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Remarkably, 3 genes tested, Iswi, Rbfox1, and RpS19a, could rescue the MB defects observed in flies expressing U2af50 RNAi to a different extent."
    explanation: >-
      Identifies downstream effectors whose restoration rescues the fly
      mushroom body defect, placing them functionally downstream of U2AF2.
  downstream:
  - target: Impaired Neurogenesis and Neurite Outgrowth
    description: >-
      Altered splicing of neural splicing regulators and other substrates
      impairs neural progenitor proliferation and neurite growth.
    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: "Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies."
      explanation: >-
        Links the splicing effectors to the neural structural defect through
        rescue in the fly.
- name: Impaired Neurogenesis and Neurite Outgrowth
  description: >-
    Neurons differentiated from human pluripotent stem cells carrying the
    hyper-recurrent Arg149Trp or Arg150Cys variant have shorter neurites, and
    neural knockdown of the fly ortholog U2af50 reduces neural progenitor
    proliferation, shrinks the mushroom body, and produces heat-induced
    seizure-like paralysis and social deficits, none of which the patient
    variants fully rescue.
  role: downstream_consequence
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron projection development
    term:
      id: GO:0031175
      label: neuron projection development
    modifier: DECREASED
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants."
    explanation: Isogenic human neuron model of the two commonest variants.
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "These results strongly suggest that, while WT U2AF2 could largely replace U2af50 in flies, the 2 variants were partial LoF alleles."
    explanation: >-
      Rescue experiments in neural U2af50-knockdown flies classify the
      recurrent variants as partial loss of function.
  downstream:
  - target: Global Developmental 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: IN_VITRO
      snippet: "Together, these data suggest that U2AF2 has an important role in neurogenesis and neuritogenesis and a partial LoF effect for both variants, which would ultimately alter neuronal connectivity and network activity."
      explanation: >-
        The authors connect the neuritogenesis defect to altered neuronal
        connectivity; the step to the clinical delay is inferential.
  - 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: >-
        Fly learning-centre defects are offered as the counterpart of the
        intellectual impairment; stated by the authors as a possibility.
  - target: Seizures
    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: "At 6 minutes, 60% of U2af50-knockdown flies were immobile, whereas only 20% of the WT flies showed the heat-induced paralysis"
      explanation: >-
        Motor-neuron knockdown of the fly ortholog produces heat-induced
        seizure-like paralysis, which the authors relate to the frequent
        (often febrile) seizures in patients.
  - target: Autistic Behavior
    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: "Similarly, knockdown of U2af50 in the MB resulted in increased social aggregation in adult female flies."
      explanation: >-
        A social-behaviour deficit in the fly model is the experimental
        counterpart of the autistic features.
  - target: Thin Corpus Callosum
    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: "Taken together, these phenotypes observed suggest that U2af50 played an essential role in the Drosophila nervous system, and, most important, they mimic some key brain malformations observed in patients carrying U2AF2 variants."
      explanation: >-
        The authors relate the fly brain structural defects to the brain
        malformations in patients, of which the thin corpus callosum is the
        most frequent; the correspondence is by analogy.
phenotypes:
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Developmental delay, mild to severe, present in essentially every
    individual surviving infancy and usually global, involving speech and
    language, cognition, motor skills and social behaviour.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental 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: "All individuals except 2 (individuals 27 and 33, who died before 6 months of age) had developmental delay ranging from mild to severe, and most of them had global developmental delay involving speech and language, cognition, motor skills, and social behavior."
    explanation: Cohort of 46 individuals.
  - reference: PMID:34112922
    reference_title: "Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient showed global developmental delay, intellectual disability, epilepsy, short stature, microcephaly, facial dysmorphism"
    explanation: First clinically detailed case report (Arg149Trp).
- category: Neurodevelopmental
  name: Delayed Speech and Language Development
  description: Speech and language delay as part of the global delay.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data reveal a neurodevelopmental phenotype associated with U2AF2 de novo missense variants, with core features of global developmental, speech, and motor delays"
    explanation: Speech delay is named among the core features.
  - reference: PMID:36747105
    reference_title: "A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum"
    explanation: Language delay in an independent case.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: Intellectual disability, mild in most and severe in about a quarter of assessed individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  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: "ID was present in 30 of 34 (88%) of the individuals assessed, with a severity ranging from mild (n = 22) to severe (n = 8) ID."
    explanation: Gives frequency (88%) and severity range.
- category: Neurological
  name: Hypotonia
  description: Muscular hypotonia.
  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: "Hypotonia was identified in 25 of 37 probands (68%)."
    explanation: Frequency in the cohort.
- category: Neurological
  name: Seizures
  description: >-
    Seizures in just over half of individuals; about two thirds of those with
    seizures had febrile seizures, and generalized tonic-clonic seizures also
    occur.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  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: "Seizures occurred in 23 of 41 participants (56%), 15 of whom had febrile seizures (65%)."
    explanation: Frequency of seizures and of the febrile subset.
- category: Neurological
  name: Febrile Seizures
  description: Febrile seizures in childhood, the commonest seizure type reported.
  phenotype_term:
    preferred_term: Febrile seizure
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  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: "Seizures occurred in 23 of 41 participants (56%), 15 of whom had febrile seizures (65%)."
    explanation: >-
      15 of 41 participants (about 37%) had febrile seizures.
- category: Neurological
  name: Thin Corpus Callosum
  description: >-
    Abnormal brain MRI in about 40% of imaged individuals; a thin or poorly
    developed corpus callosum is the most frequent finding, with delayed
    myelination, ventricular asymmetry, hemispheric atrophy, absent olfactory
    bulbs and dysmorphic inferior frontal gyri also reported.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI was performed in 34 probands, and 14 (41%) had abnormal imaging findings, including delayed myelination, ventricle asymmetry, atrophy of the cerebral hemisphere, absent olfactory bulbs and tracts, dysmorphic inferior frontal gyri, and, the most prevalent finding, a thin or poorly developed corpus collosum (9 of 14 individuals)."
    explanation: >-
      9 of 34 imaged individuals (about 26%) had a thin or poorly developed
      corpus callosum.
  - reference: PMID:34112922
    reference_title: "Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum"
    explanation: Thin corpus callosum in the first case report.
- category: Neurological
  name: Delayed CNS Myelination
  description: Delayed myelination on brain MRI in a subset of imaged individuals.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "had abnormal imaging findings, including delayed myelination, ventricle asymmetry, atrophy of the cerebral hemisphere"
    explanation: Delayed myelination is among the reported MRI findings.
- category: Behavioral
  name: Autistic Behavior
  description: Autism spectrum disorder or autistic features in over a quarter of individuals.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A formal diagnosis of ASD was made in 6 individuals, with 5 additional individuals having autistic features (11 of 39)"
    explanation: 11 of 39 individuals (28%).
- category: Behavioral
  name: Behavioral Abnormality
  description: Behavioural disturbances in about two thirds of individuals.
  phenotype_term:
    preferred_term: Behavioral disturbance
    term:
      id: HP:0000708
      label: Atypical behavior
  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: "with a total of 64% (25 of 39) of the participants identified as having behavioral issues"
    explanation: Frequency of behavioural issues in the cohort.
- category: Growth
  name: Short Stature
  description: Postnatal short stature (height at or below -2 SD).
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten individuals had postnatal short stature (height ≤ –2 SD; 10 of 40), 5 individuals had microcephaly"
    explanation: 10 of 40 individuals (25%).
- category: Growth
  name: Microcephaly
  description: >-
    Microcephaly in a minority of individuals; macrocephaly has also been
    reported, so head size is variable.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "5 individuals had microcephaly (head circumference [HC] ≤ –2 SD), 3 individuals had macrocephaly (HC ≥ +2 SD), and 4 individuals had obesity."
    explanation: Microcephaly in 5 of the cohort, with macrocephaly in 3.
- category: Craniofacial
  name: Hypertelorism
  description: Part of the shared facial gestalt.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical photographs of 19 participants show several shared craniofacial features, including a prominent/broad forehead, a high anterior hairline, deep-set eyes, hypertelorism, short palpebral fissures"
    explanation: Hypertelorism is among the shared facial features.
- category: Craniofacial
  name: Deeply Set Eyes
  description: Part of the shared facial gestalt.
  phenotype_term:
    preferred_term: Deep-set eyes
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical photographs of 19 participants show several shared craniofacial features, including a prominent/broad forehead, a high anterior hairline, deep-set eyes"
    explanation: Deep-set eyes are among the shared facial features.
- category: Craniofacial
  name: Micrognathia
  description: Part of the shared facial gestalt.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "a narrow nasal bridge with an upturned nose, thin upper lips, micrognathia, a wide mouth, wide-spaced teeth, and a short neck"
    explanation: Micrognathia is among the shared facial features.
- category: Ophthalmologic
  name: Ptosis
  description: Bilateral ptosis, with intermittent exotropia, in the first reported case.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:34112922
    reference_title: "Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum"
    explanation: Single-case observation.
- category: Cardiovascular
  name: Congenital Heart Abnormality
  description: >-
    Heart abnormalities in about a quarter of individuals; the cohort summary
    does not specify the lesions, so the binding is the general term.
  phenotype_term:
    preferred_term: Heart abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37962958
    reference_title: "Spliceosome malfunction causes neurodevelopmental disorders with overlapping features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 11 of 42 individuals (26%), heart abnormalities were reported."
    explanation: Frequency in the cohort; lesion types not given in the text.
  - reference: PMID:42135263
    reference_title: "De Novo 2.2 Mb 19q13.42-q13.43 Microdeletion Encompassing U2AF2: Support for a Haploinsufficiency Model."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with intellectual disability, epilepsy, corpus callosum hypoplasia, dysmorphic features, and congenital heart disease"
    explanation: >-
      Congenital heart disease in a patient with a whole-gene deletion; the
      deletion spans other genes, so attribution to U2AF2 is not certain.
genetic:
- name: U2AF2
  gene_term:
    preferred_term: U2AF2
    term:
      id: hgnc:23156
      label: U2AF2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    U2 small nuclear RNA auxiliary factor 2, the 65 kDa U2AF subunit. Variants
    are heterozygous and nearly all de novo. Missense variants cluster in the
    RRM1 and RRM2 RNA recognition motifs; seven recurrent variants account for
    about two thirds of individuals in the largest cohort, with Arg149Trp and
    Arg150Cys/His as hotspots. Fly rescue experiments classify the recurrent
    missense variants as partial loss of function. A presumed missense variant
    (c.603G>T) instead causes exon 6 skipping and an in-frame deletion, and a
    2.2 Mb de novo deletion spanning U2AF2 has been reported with an
    overlapping phenotype, suggesting haploinsufficiency may also cause
    disease. No ClinGen gene-disease validity record for U2AF2 is present in
    the local structured-source cache.
  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)"
    explanation: Largest cohort establishing the gene-disease association.
  - reference: PMID:34112922
    reference_title: "Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report an individual with a de novo U2AF2 variant (c.445C>T, p.(Arg149Trp)) using trio-based whole-exome sequencing."
    explanation: First clinically detailed de novo case.
  - reference: PMID:37092751
    reference_title: "U2AF2 variant in a patient with developmental delay, dysmorphic features, and epilepsy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a patient with a de novo missense variant in U2AF2, the second case report of the same variant, and third case report overall."
    explanation: Independent recurrence of the same variant.
  variants:
  - name: p.(Arg149Trp)
    description: >-
      c.445C>T, the commonest recurrent missense variant, in RRM1. Reduces
      polypyrimidine-tract RNA binding and is a partial loss-of-function
      allele in Drosophila rescue assays.
    evidence:
    - reference: PMID:39388459
      reference_title: "Recurrent Neurodevelopmentally Associated Variants of the Pre-mRNA Splicing Factor U2AF2 Alter RNA Binding Affinities and Interactions."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Two U2AF2 residues harbor outstanding, recurrent mutations among different patients (Figure 1A): Arg149, which is changed to tryptophan in 85% of cases"
      explanation: Recurrence of the Arg149Trp change among patients, cited as background in a biochemical study.
    - reference: PMID:41090043
      reference_title: "U2AF2 Missense Variant Associated With Epilepsy and Systemic Dysmorphism: Report of Two Cases and Literature Review."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recurrent U2AF2 c.445C>T variant in two cases with systemic dysmorphism, epilepsy, and neurodevelopmental regression"
      explanation: Two further cases with the same variant.
  - name: c.603G>T (exon 6 skipping)
    description: >-
      Presumed missense variant shown in patient lymphoblastoid cells to cause
      exon 6 skipping and an in-frame deletion (p.E163_E201del).
    evidence:
    - reference: PMID:36747105
      reference_title: "A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del)"
      explanation: RNA and protein analysis in patient-derived cells.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous variants, nearly all arising de novo; no familial
    transmission has been reported in the cited cohort.
  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, all of which are involved in the pre-mRNA splicing machinery."
    explanation: Heterozygous de novo variants, consistent with dominant inheritance.
animal_models:
- name: Drosophila neural U2af50 knockdown
  species: Fruit fly
  genotype: elav-Gal4 driven U2af50 RNAi, with or without UAS-U2AF2 WT, Arg149Trp or Arg150Cys
  publication: PMID:37962958
  description: >-
    Pan-neural, mushroom-body and motor-neuron knockdown of the fly U2AF2
    ortholog, with rescue by wild-type or patient-variant human U2AF2.
  modeled_mechanisms:
  - target: Impaired Neurogenesis and Neurite Outgrowth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Knockdown reduces brain progenitor proliferation and mushroom body size
      and produces seizure-like paralysis; patient variants rescue these only
      partly.
    limitations: >-
      RNAi knockdown (about 49% reduction) models reduced dosage rather than
      the heterozygous missense lesion directly; the mushroom body has no
      direct human counterpart, and behaviour and seizure 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: u2af2_dosage_versus_altered_function
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Germline U2AF2 RNA Recognition Motif Variant
  - pathophysiology#Altered Splicing of Neurodevelopmental RNA-Binding Protein Transcripts
  prompt: >-
    Do the recurrent RRM missense variants act purely as partial loss of
    function equivalent to reduced U2AF2 dosage, and which human neural
    transcripts mis-spliced by them account for the brain phenotype?
  rationale: >-
    Fly rescue experiments classify the recurrent variants as partial loss of
    function, and a whole-gene deletion produces an overlapping phenotype, but
    the missense proteins are expressed at normal levels and missense variants
    cluster at RNA-contacting residues, which leaves open a dominant or
    substrate-specific component. The splicing targets identified so far come
    from fly brain knockdown and from non-neural human cell lines; no
    transcriptome of patient-derived neurons carrying the variants has
    identified the disease-relevant human splicing events. The facial,
    growth and cardiac features have no mechanistic node in this entry for the
    same reason.
  evidence:
  - reference: PMID:42135263
    reference_title: "De Novo 2.2 Mb 19q13.42-q13.43 Microdeletion Encompassing U2AF2: Support for a Haploinsufficiency Model."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's clinical features overlap substantially with those reported in individuals harboring heterozygous U2AF2 variants, supporting haploinsufficiency as a plausible disease mechanism."
    explanation: >-
      Supports a dosage model, while the deletion's other genes make this
      indirect.