Nager Acrofacial Dysostosis

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Mappings

MONDO

MONDO:0007943 Nager acrofacial dysostosis

MONDO:0007943 is the disease concept for Nager syndrome, cross-referenced to OMIM:154400 and Orphanet:245.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Most SF3B4 variants are frameshifts acting through haploinsufficiency, and most cases are sporadic de novo events; vertical transmission from an affected parent is documented.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Most cases are sporadic, and both autosomal-dominant and autosomal-recessive inheritances have been reported"

States the inheritance patterns reported for the syndrome.

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Discussions and Knowledge Gaps

2

Why does heterozygous loss of sf3b4 cause no craniofacial phenotype in Xenopus tropicalis when the same half dose of SF3B4 causes Nager syndrome in humans, and what does that imply for using the frog null as a model of a human haploinsufficiency disorder?

HUMAN MODEL MISMATCH OPEN nager_sf3b4_dose_species_mismatch

Attached to

pathophysiology#SF3B4 Haploinsufficiency animal_models#Xenopus tropicalis sf3b4 CRISPR mutant line

Human Nager syndrome is a dominant haploinsufficiency: one truncating SF3B4 allele is enough. In the frog, heterozygotes are transcriptionally and morphologically near-normal and only homozygous nulls show the crest and cartilage phenotype — which the authors themselves read as an autosomal recessive mode in X. tropicalis. So the genotype that models the disease biochemically is not the genotype that models it clinically. Either the frog tolerates a lower dose of Sf3b4 than humans do, or something outside gene dosage — a modifier, a threshold effect, or a difference in how long cranial crest is exposed to the deficit — sets the human threshold. Until that is resolved, mechanisms read off the null should be treated as showing what losing Sf3b4 can do, not as showing what patients' cells are doing. The same question sits underneath the disease's central puzzle, which is why a core spliceosome component fails in one lineage only.

Show evidence (2 references)

PMID:40126363 SUPPORT Model Organism

"our data indicate that sf3b4 haploinsufficiency is compatible with normal development in X. tropicalis, whereas homozygous deletion of sf3b4 is detrimental to survival and the formation of NC-derived cartilage progenitors, consistent with an autosomal recessive mode of inheritance"

States the species difference in dose sensitivity in the authors' own terms.

PMID:22541558 SUPPORT Human Clinical

"These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4."

The human side of the mismatch — one allele is sufficient to cause disease in people.

Why does reduced dose of a ubiquitously required core spliceosome component damage cranial neural crest specifically, rather than every dividing tissue?

KNOWLEDGE GAP OPEN nager_spliceosome_lineage_selectivity

Attached to

pathophysiology#Aberrant Pre-mRNA Splicing and Exon Skipping

This is the defining unanswered question of the spliceosomopathies, and nothing in this entry's pathophysiology answers it — the chain from reduced SF3B4 to shortened crest streams describes what happens without explaining why the crest is where it happens. Candidate explanations include an unusually high transcriptional demand in migrating crest, particular sensitivity of specific transcripts to branch-point recognition, and a p53-linked apoptotic threshold that crest cells cross first. The frog line gives the tools to test these, since it separates the splicing change in time from the cellular failure.

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"It is especially puzzling that variants of a core component of this largely ubiquitous cellular machinery result in such an exquisitely cell type- and lineage-specific defect."

States the gap in the authors' own words.

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Pathophysiology

4

SF3B4 Haploinsufficiency

Heterozygous SF3B4 variants — nearly all frameshifts predicted to encode truncated protein — reduce the dose of SAP49, the U2 snRNP component that binds upstream of the intronic branch point and helps tether U2 to the pre-mRNA. Roughly 60% of Nager syndrome is explained this way; the remaining 40% has no identified cause. The same gene, with more severe alleles, causes Rodriguez syndrome.

SF3B4 hgnc:10771

U2 snRNP tethering to the pre-mRNA branch point GO:0000387 ↓ DECREASED

Downstream

Aberrant Pre-mRNA Splicing and Exon Skipping Reduced U2 snRNP branch-point tethering degrades splice-site recognition, which surfaces first as skipped exons rather than as global splicing failure.

Show evidence (2 references)

PMID:22541558 SUPPORT Human Clinical

"After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts."

The discovery cohort establishing the mutation spectrum and its frameshift character.

PMID:22541558 SUPPORT Human Clinical

"These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4."

States the dosage mechanism this node asserts.

Aberrant Pre-mRNA Splicing and Exon Skipping

Loss of SF3B4 dose does not abolish splicing. It shifts splice-site choice, producing an excess of transcripts with atypically skipped exons, and only afterwards a broad dysregulation of gene expression enriched for splicing, apoptosis, cell cycle and neural crest migration. This two-step course is what turns a housekeeping defect into a developmental one.

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Animal models

Xenopus tropicalis sf3b4 CRISPR mutant line Xenopus tropicalis recapitulates Temporal RNA-seq of mutant embryos resolves the splicing lesion into an early exon-skipping phase and a later transcriptional collapse, which is the ordering this node asserts.

Downstream

Cranial Neural Crest Migration Failure and Apoptosis The transcriptional consequences of mis-splicing fall on migration and survival programmes, and the cranial neural crest is the lineage in which that shows.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"GO analysis of differentially expressed genes in sf3b4 Null embryos revealed an enrichment in terms pertaining to mRNA splicing, apoptosis, cell cycle and NC cell migration."

Names the processes the downstream transcriptional change converges on.

Cranial Neural Crest Migration Failure and Apoptosis

Neural crest is induced normally — pre-migratory markers are unaffected — and the defect appears at the migratory stage: cranial crest streams entering the branchial arches are shortened, and apoptosis rises in the head region. This is the step that makes the disease craniofacial rather than global, and the intact induction is as informative as the failed migration.

migratory cranial neural crest cell CL:0000333

neural crest cell migration GO:0001755 ↓ DECREASED apoptotic process GO:0006915 ↑ INCREASED

branchial arch UBERON:0002539

Animal models

Xenopus tropicalis sf3b4 CRISPR mutant line Xenopus tropicalis recapitulates Separates induction from migration: pre-migratory crest markers are normal, and the phenotype emerges at the migratory stage as shortened crest streams with increased head apoptosis.

Downstream

First and Second Branchial Arch Skeletal Hypoplasia Fewer crest cells reaching the arches, and fewer surviving there, leaves too little mesenchyme to build the arch-derived skeleton.

Show evidence (3 references)

PMID:40126363 SUPPORT Model Organism

"We show that in the absence of Sf3b4 function NC induction is not affected."

The negative half of the result, which localizes the defect to migration rather than specification.

PMID:40126363 SUPPORT Model Organism

"Quantification of the phenotype showed a statistically significant reduction of the NC stream length (streams 2 and 3 for sox10, and streams 3 and 4 for sox9) in Het and Null embryos compared to WT siblings"

Quantifies the shortened cranial crest streams.

PMID:40126363 SUPPORT Model Organism

"at the migratory stage (NF stage 25), there was a significant increase in apoptosis in the head region of Het and Null embryos, with a greater number of TUNEL-positive cells in the Null compared to the Het animals"

Quantifies the apoptotic component and its dose dependence.

First and Second Branchial Arch Skeletal Hypoplasia

The craniofacial structures affected in Nager syndrome — mandible, malar complex, external ear and middle-ear ossicles — are first- and second-branchial-arch derivatives built from cranial neural crest. Their hypoplasia is the anatomical substrate of both the facial appearance and the neonatal airway compromise.

embryonic cranial skeleton morphogenesis GO:0048701 ⚠ ABNORMAL chondrocyte differentiation GO:0002062 ↓ DECREASED

mandible UBERON:0001684

Animal models

Xenopus tropicalis sf3b4 CRISPR mutant line Xenopus tropicalis partially recapitulates Null embryos lose the neural-crest-derived cartilage progenitor pool that builds the arch skeleton, giving a developmental account of the craniofacial hypoplasia.

Downstream

Micrognathia Mandibular hypoplasia is the first-arch component of the arch skeletal defect.

Neonatal upper airway obstruction Micrognathia displaces the tongue base and, with trismus, obstructs the neonatal airway.

Conductive hearing impairment Middle-ear ossicles are second-arch derivatives, so their malformation produces conductive rather than sensorineural loss.

Show evidence (2 references)

PMID:40126363 SUPPORT Other

"The craniofacial structures affected in Nager syndrome are primarily derived from the first and second branchial arches"

Identifies the developmental origin of the affected structures.

PMID:40126363 SUPPORT Other

"The craniofacial skeletal structures affected in Nager syndrome are neural crest (NC)-derived."

Establishes the lineage that links the cellular node to the anatomical one.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 1

Congenital cardiac malformation OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:35331022 SUPPORT Human Clinical

"patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations"

Establishes cardiac malformation as an observed feature and records the only positional signal the pooled analysis found for it.

PMID:41667381 SUPPORT Other

"These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems."

Places cardiac among the affected systems in a review of the disease and its models.

Ear 1

Conductive hearing impairment FREQUENT HP:0000405

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"

Names the defective middle ear ossicles that underlie the conductive loss.

Eye 1

Ocular involvement OCCASIONAL Abnormal eye morphology HP:0012372

Show evidence (1 reference)

PMID:41667381 SUPPORT Other

"These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems."

Names the ocular system among those affected, without specifying which ocular finding, which is why this is graded partial.

Head and Neck 4

Micrognathia VERY_FREQUENT HP:0000347

Show evidence (2 references)

PMID:40126363 SUPPORT Other

"Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"

Lists micrognathia as a defining presenting feature.

PMID:41667381 SUPPORT Other

"Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."

A dedicated Nager syndrome review naming this as one of the two defining feature groups.

Downslanted palpebral fissures VERY_FREQUENT HP:0000494

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"

Lists downslanting palpebral fissures as a defining presenting feature.

Midface retrusion VERY_FREQUENT HP:0011800

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."

Lists midface retrusion among the characterizing features.

Trismus FREQUENT HP:0000211

Show evidence (1 reference)

PMID:18947886 SUPPORT Human Clinical

"Trismus and glossoptosis from mandibular abnormalities predisposes infants to life-threatening respiratory distress."

Names trismus as a contributor to the neonatal airway risk.

Limbs 1

Absent thumb VERY_FREQUENT HP:0009777

Show evidence (2 references)

PMID:40126363 SUPPORT Other

"Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."

Lists absent thumbs among the characterizing features.

PMID:41667381 SUPPORT Other

"Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."

A dedicated Nager syndrome review naming this as one of the two defining feature groups.

Respiratory 1

Neonatal upper airway obstruction VERY_FREQUENT Neonatal respiratory distress HP:0002643

Show evidence (1 reference)

PMID:40280475 SUPPORT Human Clinical

"Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."

Quantifies the airway intervention rates and mortality in a neonatal cohort.

Other 1

Aplasia/Hypoplasia of the radius FREQUENT HP:0006501

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."

Lists radial hypoplasia among the characterizing features.

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Genetic Associations

1

SF3B4 (Haploinsufficiency; accounts for roughly 60% of cases)

Gene: SF3B4 hgnc:10771 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:22541558 SUPPORT Human Clinical

"mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome"

The gene discovery establishing SF3B4 as the causative gene.

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Medical Actions

3

Neonatal airway stabilization and tracheostomy

Action: tracheotomy Ontology label: Tracheotomy NCIT:C15341

Securing the airway is the first priority. Intubation is difficult because trismus restricts mouth opening, and a majority of affected neonates ultimately require tracheostomy.

Show evidence (2 references)

PMID:40280475 SUPPORT Human Clinical

"Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."

Quantifies how often airway intervention is needed in this population.

PMID:18947886 SUPPORT Human Clinical

"A case of a Nager Syndrome mother delivering a similarly afflicted fetus is presented, with approaches to maintaining both tenuous airways described."

Airway management is the subject of this report; it is a single family, so it supports the practice rather than establishing an approach.

Gastrostomy feeding support

Action: gastrostomy tube placement Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Micrognathia, restricted mouth opening and a secured airway together impair oral feeding, and enteral access is commonly needed in the mandibulofacial dysostosis population.

Show evidence (1 reference)

PMID:40280475 SUPPORT Human Clinical

"Compared with infants with micrognathia, those with TCS were more likely to undergo tracheostomy (54% vs 11%) and gastrostomy tube placement (67% vs 35%)"

The reported gastrostomy rate is for the Treacher Collins arm of the same cohort, not the Nager arm, so this supports the practice in mandibulofacial dysostosis generally rather than quantifying it in Nager syndrome.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling covers de novo occurrence in most cases, autosomal dominant transmission from an affected parent, and the 40% of clinically diagnosed individuals in whom no causative variant is found.

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Most cases are sporadic, and both autosomal-dominant and autosomal-recessive inheritances have been reported"

The inheritance picture that counseling has to convey.

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Diagnosis

2

Molecular genetic testing of SF3B4

Sequencing of SF3B4 confirms the diagnosis in roughly 60% of clinically diagnosed individuals; a negative result does not exclude Nager syndrome, since 40% of cases have no identified cause.

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"The remaining 40% of cases are of unknown cause."

States the diagnostic yield limit that this recommendation turns on.

Clinical recognition of the acrofacial pattern

The diagnosis is made clinically from the combination of mandibulofacial dysostosis with preaxial upper-limb anomalies. It is the limb component that separates Nager syndrome from the mandibulofacial dysostoses it otherwise resembles, so a thumb and forearm examination is part of the craniofacial assessment rather than an add-on.

Show evidence (2 references)

PMID:41667381 SUPPORT Other

"Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."

States the two-part clinical pattern the diagnosis rests on.

PMID:35331022 SUPPORT Human Clinical

"Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies."

Independently states the same craniofacial-plus-preaxial-limb definition.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Roughly 100 cases reported worldwide as of 2025; no population-based rate estimate exists, so the class is assigned from the case count rather than from a measured rate.

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Nager syndrome is a rare disorder, with approximately 100 reported cases ever, worldwide."

Gives the total reported case count that this record summarizes.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Nager Acrofacial Dysostosis:

Treacher Collins syndrome

Overlapping Features Shares the mandibulofacial dysostosis pattern but lacks preaxial limb involvement; the thumb and radial defects are what make Nager syndrome acrofacial. Neonatal courses also differ — tracheostomy and mortality rates are substantially higher in Nager syndrome.

Show evidence (1 reference)

PMID:40280475 SUPPORT Human Clinical

"Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."

Quantifies the neonatal difference between the two syndromes in a shared cohort.

Rodriguez syndrome

Overlapping Features Also caused by SF3B4 variants, with the same craniofacial pattern but more severe, and additionally involving the lower limbs, heart and forebrain.

Show evidence (1 reference)

PMID:40126363 SUPPORT Other

"Rodriguez syndrome (OMIM #201170) is another condition due to mutations in SF3B4"

Establishes the shared gene that makes this the closest allelic differential.

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Animal Models

1

Xenopus tropicalis sf3b4 CRISPR mutant line Germline gene-edited mutant line

A stable frog mutant line built to ask why a ubiquitous splicing factor produces a lineage-restricted disease. Its answer has two parts: the splicing lesion appears first as excess exon skipping and only later as broad transcriptional dysregulation, and the cellular failure is in cranial neural crest migration and survival rather than in crest induction. The line also delivers the field's clearest human-model mismatch — heterozygous frogs are indistinguishable from wild type and form normal craniofacial cartilage, while the corresponding human genotype is the disease.

Species

Xenopus tropicalis

Genotype

CRISPR/Cas9-generated sf3b4 deletion, heterozygous and homozygous null, with wild-type siblings

Genes

SF3B4 hgnc:10771

Publication

PMID:40126363

Pathograph links

Aberrant Pre-mRNA Splicing and Exon Skipping recapitulates fidelity: high Temporal RNA-seq of mutant embryos resolves the splicing lesion into an early exon-skipping phase and a later transcriptional collapse, which is the ordering this node asserts.

Limitations: The splicing phenotype is reported for null embryos; heterozygotes differ only minimally from wild type at the transcriptome level, so the model characterizes what total loss of Sf3b4 does to splicing rather than what the patient's half dose does.

Readouts

Genes with atypical skipped exons in mutant embryos

Direction: INCREASED

Interpretation: Exon skipping rises before general gene dysregulation, identifying it as the primary molecular consequence rather than a downstream effect.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"Temporal RNA-sequencing analyses of mutant embryos identified an increase in exon-skipping events, followed by important transcriptional changes associated with an enrichment for terms consistent with defects in NC cell migration and survival."

Reports both the measured increase and its temporal precedence.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"we generated a Xenopus tropicalis sf3b4 mutant line using CRISPR/Cas9 gene-editing technology"

Establishes the model as a germline edit of the disease gene rather than a transient knockdown.

Cranial Neural Crest Migration Failure and Apoptosis recapitulates fidelity: high Separates induction from migration: pre-migratory crest markers are normal, and the phenotype emerges at the migratory stage as shortened crest streams with increased head apoptosis.

Limitations: Severity is dose-dependent and the informative phenotype is largely in the null, which is not the human genotype. The apoptotic component is scored by TUNEL in the whole head region rather than in identified crest cells, so apoptosis of crest cells specifically is inferred.

Readouts

Cranial neural crest stream length (sox9, sox10)

Direction: DECREASED

Interpretation: Shorter streams at the migratory stage, with normal pre-migratory markers, place the defect in migration rather than specification.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"Quantification of the phenotype showed a statistically significant reduction of the NC stream length (streams 2 and 3 for sox10, and streams 3 and 4 for sox9) in Het and Null embryos compared to WT siblings"

The quantified migration readout.

TUNEL-positive cells in the head region

Direction: INCREASED

Interpretation: Cell death rises only once migration begins, matching the stage at which the migration defect appears.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"at the migratory stage (NF stage 25), there was a significant increase in apoptosis in the head region of Het and Null embryos, with a greater number of TUNEL-positive cells in the Null compared to the Het animals"

The quantified survival readout and its stage dependence.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"We show that in the absence of Sf3b4 function NC induction is not affected."

The control result that makes the migration interpretation possible.

First and Second Branchial Arch Skeletal Hypoplasia partially recapitulates fidelity: moderate Null embryos lose the neural-crest-derived cartilage progenitor pool that builds the arch skeleton, giving a developmental account of the craniofacial hypoplasia.

Limitations: Null animals die before the tadpole stage, so the mature craniofacial skeleton cannot be scored in the genotype that shows the phenotype; and the genotype that survives, the heterozygote, forms normal cartilage. The readouts are larval frog cartilages, which do not map one-to-one onto the human mandible, malar complex and ossicles.

Readouts

Craniofacial cartilage formation in heterozygous tadpoles

Direction: UNCHANGED

Interpretation: A negative result, and the crux of the model's limitation: the genotype that corresponds to the human disease produces no craniofacial phenotype in the frog.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"sf3b4 Null animals failed to survive beyond the tadpole stage, but Het tadpoles were indistinguishable from their WT siblings, forming largely normal craniofacial cartilages."

Records both the null lethality and the absence of a heterozygous phenotype.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"Homozygous deletion of sf3b4 is detrimental to the development of cranial neural crest (NC)-derived cartilage progenitors."

Supports the model reporting on the cartilage progenitor pool behind this node.

Show evidence (1 reference)

PMID:40126363 SUPPORT Model Organism

"We propose that disruption of these processes may underly the pathogenesis of Nager and Rodriguez syndromes."

The authors offer the link to human pathogenesis as a proposal, which is the level of claim this model supports.

{ }

Source YAML

click to show

name: Nager Acrofacial Dysostosis
creation_date: '2026-08-27T14:30:00Z'
description: >-
  Nager acrofacial dysostosis is the archetype of the acrofacial dysostoses: a
  congenital malformation syndrome combining mandibulofacial dysostosis
  (downslanted palpebral fissures, malar hypoplasia, micrognathia, external ear
  and middle-ear ossicle malformation) with preaxial upper-limb defects
  (hypoplastic or absent thumbs, radial hypoplasia). Roughly 60% of cases are
  caused by haploinsufficiency of SF3B4, which encodes SAP49, a component of the
  U2 subunit of the major spliceosome. The central mechanistic puzzle of the
  disease is why loss of one copy of a ubiquitous core splicing factor produces a
  defect confined to cranial neural crest and its derivatives; the disease is
  therefore curated as a spliceosomopathy whose selectivity, not whose
  biochemistry, is the open question. The neonatal course is dominated by
  airway obstruction from micrognathia, glossoptosis and trismus.
category: Congenital
parents:
- Acrofacial dysostosis
- Mandibulofacial dysostosis
- Spliceosomopathy
synonyms:
- Nager syndrome
- AFD1
- acrofacial dysostosis 1, Nager type
- mandibulofacial dysostosis with preaxial limb anomalies
- preaxial mandibulofacial dysostosis
disease_term:
  preferred_term: Nager acrofacial dysostosis
  term:
    id: MONDO:0007943
    label: Nager acrofacial dysostosis
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007943
      label: Nager acrofacial dysostosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007943 is the disease concept for Nager syndrome, cross-referenced
      to OMIM:154400 and Orphanet:245.
references:
- reference: PMID:22541558
  title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
- reference: PMID:35331022
  title: "SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome."
- reference: PMID:41667381
  title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most SF3B4 variants are frameshifts acting through haploinsufficiency, and
    most cases are sporadic de novo events; vertical transmission from an
    affected parent is documented.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most cases are sporadic, and both autosomal-dominant and autosomal-recessive inheritances have been reported"
    explanation: States the inheritance patterns reported for the syndrome.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Roughly 100 cases reported worldwide as of 2025; no population-based rate
    estimate exists, so the class is assigned from the case count rather than
    from a measured rate.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager syndrome is a rare disorder, with approximately 100 reported cases ever, worldwide."
    explanation: Gives the total reported case count that this record summarizes.
pathophysiology:
- name: SF3B4 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Heterozygous SF3B4 variants — nearly all frameshifts predicted to encode
    truncated protein — reduce the dose of SAP49, the U2 snRNP component that
    binds upstream of the intronic branch point and helps tether U2 to the
    pre-mRNA. Roughly 60% of Nager syndrome is explained this way; the remaining
    40% has no identified cause. The same gene, with more severe alleles, causes
    Rodriguez syndrome.
  genes:
  - preferred_term: SF3B4
    term:
      id: hgnc:10771
      label: SF3B4
  biological_processes:
  - preferred_term: U2 snRNP tethering to the pre-mRNA branch point
    modifier: DECREASED
    term:
      id: GO:0000387
      label: spliceosomal snRNP assembly
  evidence:
  - reference: PMID:22541558
    reference_title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts."
    explanation: The discovery cohort establishing the mutation spectrum and its frameshift character.
  - reference: PMID:22541558
    reference_title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4."
    explanation: States the dosage mechanism this node asserts.
  downstream:
  - target: Aberrant Pre-mRNA Splicing and Exon Skipping
    description: >-
      Reduced U2 snRNP branch-point tethering degrades splice-site recognition,
      which surfaces first as skipped exons rather than as global splicing
      failure.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Temporal RNA-sequencing analyses of mutant embryos identified an increase in exon-skipping events, followed by important transcriptional changes associated with an enrichment for terms consistent with defects in NC cell migration and survival."
      explanation: Supplies the ordering — splicing change first, transcriptional dysregulation after — from the frog mutant time course.
- name: Aberrant Pre-mRNA Splicing and Exon Skipping
  biological_scale: MOLECULAR
  description: >-
    Loss of SF3B4 dose does not abolish splicing. It shifts splice-site choice,
    producing an excess of transcripts with atypically skipped exons, and only
    afterwards a broad dysregulation of gene expression enriched for splicing,
    apoptosis, cell cycle and neural crest migration. This two-step course is
    what turns a housekeeping defect into a developmental one.
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    modifier: ABNORMAL
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GO analysis of differentially expressed genes in sf3b4 Null embryos revealed an enrichment in terms pertaining to mRNA splicing, apoptosis, cell cycle and NC cell migration."
    explanation: Names the processes the downstream transcriptional change converges on.
  downstream:
  - target: Cranial Neural Crest Migration Failure and Apoptosis
    description: >-
      The transcriptional consequences of mis-splicing fall on migration and
      survival programmes, and the cranial neural crest is the lineage in which
      that shows.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "NC cell migration is disrupted at the tailbud stage, and coupled with an increase in apoptosis in the head region, a phenotype that is much more pronounced in Null than in Het animals."
      explanation: Establishes the edge from the splicing lesion to the two cellular failures.
- name: Cranial Neural Crest Migration Failure and Apoptosis
  biological_scale: CELLULAR
  description: >-
    Neural crest is induced normally — pre-migratory markers are unaffected — and
    the defect appears at the migratory stage: cranial crest streams entering the
    branchial arches are shortened, and apoptosis rises in the head region. This
    is the step that makes the disease craniofacial rather than global, and the
    intact induction is as informative as the failed migration.
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    modifier: DECREASED
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  locations:
  - preferred_term: branchial arch
    term:
      id: UBERON:0002539
      label: pharyngeal arch
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that in the absence of Sf3b4 function NC induction is not affected."
    explanation: The negative half of the result, which localizes the defect to migration rather than specification.
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Quantification of the phenotype showed a statistically significant reduction of the NC stream length (streams 2 and 3 for sox10, and streams 3 and 4 for sox9) in Het and Null embryos compared to WT siblings"
    explanation: Quantifies the shortened cranial crest streams.
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "at the migratory stage (NF stage 25), there was a significant increase in apoptosis in the head region of Het and Null embryos, with a greater number of TUNEL-positive cells in the Null compared to the Het animals"
    explanation: Quantifies the apoptotic component and its dose dependence.
  downstream:
  - target: First and Second Branchial Arch Skeletal Hypoplasia
    description: >-
      Fewer crest cells reaching the arches, and fewer surviving there, leaves
      too little mesenchyme to build the arch-derived skeleton.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous deletion of sf3b4 is detrimental to the development of cranial neural crest (NC)-derived cartilage progenitors."
      explanation: Connects the migration and survival failure to the loss of the cartilage progenitor pool.
- name: First and Second Branchial Arch Skeletal Hypoplasia
  biological_scale: TISSUE
  description: >-
    The craniofacial structures affected in Nager syndrome — mandible, malar
    complex, external ear and middle-ear ossicles — are first- and
    second-branchial-arch derivatives built from cranial neural crest. Their
    hypoplasia is the anatomical substrate of both the facial appearance and the
    neonatal airway compromise.
  biological_processes:
  - preferred_term: embryonic cranial skeleton morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048701
      label: embryonic cranial skeleton morphogenesis
  - preferred_term: chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  locations:
  - preferred_term: mandible
    term:
      id: UBERON:0001684
      label: mandible
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The craniofacial structures affected in Nager syndrome are primarily derived from the first and second branchial arches"
    explanation: Identifies the developmental origin of the affected structures.
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The craniofacial skeletal structures affected in Nager syndrome are neural crest (NC)-derived."
    explanation: Establishes the lineage that links the cellular node to the anatomical one.
  downstream:
  - target: Micrognathia
    description: Mandibular hypoplasia is the first-arch component of the arch skeletal defect.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"
      explanation: Lists micrognathia among the defining features of the syndrome.
  - target: Neonatal upper airway obstruction
    description: >-
      Micrognathia displaces the tongue base and, with trismus, obstructs the
      neonatal airway.
    evidence:
    - reference: PMID:18947886
      reference_title: "Airway management in Nager Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Trismus and glossoptosis from mandibular abnormalities predisposes infants to life-threatening respiratory distress."
      explanation: States the mechanical route from mandibular hypoplasia to airway compromise.
  - target: Conductive hearing impairment
    description: >-
      Middle-ear ossicles are second-arch derivatives, so their malformation
      produces conductive rather than sensorineural loss.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"
      explanation: Lists defective middle ear ossicles among the defining features.
phenotypes:
- name: Micrognathia
  category: Craniofacial
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Severe mandibular hypoplasia, the feature that drives the neonatal airway
    course and distinguishes the severity of Nager syndrome from milder
    mandibulofacial dysostoses.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"
    explanation: Lists micrognathia as a defining presenting feature.
  - reference: PMID:41667381
    reference_title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."
    explanation: A dedicated Nager syndrome review naming this as one of the two defining feature groups.
- name: Downslanted palpebral fissures
  category: Craniofacial
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Downward-slanting palpebral fissures, part of the mandibulofacial dysostosis pattern.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"
    explanation: Lists downslanting palpebral fissures as a defining presenting feature.
- name: Midface retrusion
  category: Craniofacial
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Retrusion of the midface with malar hypoplasia.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."
    explanation: Lists midface retrusion among the characterizing features.
- name: Absent thumb
  category: Skeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Hypoplastic or absent thumbs — the preaxial upper-limb defect that separates
    acrofacial dysostosis from isolated mandibulofacial dysostosis such as
    Treacher Collins syndrome.
  phenotype_term:
    preferred_term: Absent thumb
    term:
      id: HP:0009777
      label: Absent thumb
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."
    explanation: Lists absent thumbs among the characterizing features.
  - reference: PMID:41667381
    reference_title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."
    explanation: A dedicated Nager syndrome review naming this as one of the two defining feature groups.
- name: Aplasia/Hypoplasia of the radius
  category: Skeletal
  frequency: FREQUENT
  diagnostic: true
  description: Radial hypoplasia accompanying the thumb defect on the preaxial side of the forearm.
  phenotype_term:
    preferred_term: Radial hypoplasia
    term:
      id: HP:0006501
      label: Aplasia/Hypoplasia of the radius
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager and Rodriguez syndromes are rare craniofacial and limb disorders characterized by midface retrusion, micrognathia, absent thumbs and radial hypoplasia."
    explanation: Lists radial hypoplasia among the characterizing features.
- name: Conductive hearing impairment
  category: Otolaryngologic
  frequency: FREQUENT
  description: >-
    Conductive loss from malformed middle-ear ossicles, which are branchial arch
    derivatives affected by the same crest deficit as the facial skeleton.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals with Nager syndrome specifically present with downslanting palpebral fissures, midface retrusion, micrognathia, defective middle ear ossicles, and hypoplastic or absent thumbs"
    explanation: Names the defective middle ear ossicles that underlie the conductive loss.
- name: Trismus
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Restricted mouth opening, which compounds the airway difficulty and makes
    intubation hazardous.
  phenotype_term:
    preferred_term: Trismus
    term:
      id: HP:0000211
      label: Trismus
  evidence:
  - reference: PMID:18947886
    reference_title: "Airway management in Nager Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trismus and glossoptosis from mandibular abnormalities predisposes infants to life-threatening respiratory distress."
    explanation: Names trismus as a contributor to the neonatal airway risk.
- name: Neonatal upper airway obstruction
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >-
    Life-threatening neonatal airway obstruction is the dominant early problem.
    In a multicentre neonatal cohort, 91% of Nager syndrome infants were
    intubated at birth and 73% received a tracheostomy, with a mortality
    substantially above that of Treacher Collins syndrome.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:40280475
    reference_title: "Management and Outcomes of Neonates with Treacher Collins and Nager Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."
    explanation: Quantifies the airway intervention rates and mortality in a neonatal cohort.
- name: Congenital cardiac malformation
  category: Cardiac
  frequency: OCCASIONAL
  description: >-
    Cardiac malformations occur in a minority of patients and were enriched among
    those carrying SF3B4 variants in exons 2 and 3 in a pooled literature series.
    Cardiac involvement is also one of the systems the model literature converges
    on.
  phenotype_term:
    preferred_term: Congenital cardiac malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:35331022
    reference_title: "SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations"
    explanation: >-
      Establishes cardiac malformation as an observed feature and records the
      only positional signal the pooled analysis found for it.
  - reference: PMID:41667381
    reference_title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems."
    explanation: Places cardiac among the affected systems in a review of the disease and its models.
- name: Ocular involvement
  category: Ophthalmologic
  frequency: OCCASIONAL
  description: >-
    Ocular findings sit alongside the auditory ones among the sensory systems
    affected by SF3B4 deficiency. Recorded here at the level the source supports
    — that the ocular system is involved — rather than as a specific lesion.
  phenotype_term:
    preferred_term: Abnormal eye morphology
    term:
      id: HP:0012372
      label: Abnormal eye morphology
  evidence:
  - reference: PMID:41667381
    reference_title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems."
    explanation: >-
      Names the ocular system among those affected, without specifying which
      ocular finding, which is why this is graded partial.
genetic:
- name: SF3B4
  gene_term:
    preferred_term: SF3B4
    term:
      id: hgnc:10771
      label: SF3B4
  association: Haploinsufficiency; accounts for roughly 60% of cases
  relationship_type: CAUSATIVE
  notes: >-
    Nearly all reported variants are frameshifts predicted to truncate SAP49.
    More severe SF3B4 alleles cause Rodriguez syndrome, which shares the
    craniofacial pattern but adds lower-limb anomalies, cardiac defects and
    arhinencephaly. A pooled genotype-phenotype analysis of 84 patients found no
    significant overall association, with two soft signals: frameshift variants
    predicted to trigger nonsense-mediated decay trended more severe, and
    variants in exons 2 and 3 carried more cardiac malformations.
  case_fractions:
  - population: FORGE Canada / NIH Centers for Mendelian Genomics validation cohort
    case_fraction_percent: 57.0
    cohort_size: 35
    notes: >-
      20 of 35 families in the discovery study's validation cohort. Recorded from
      the primary source rather than from the rounded figure quoted downstream.
    evidence:
    - reference: PMID:22541558
      reference_title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts."
      explanation: The discovery cohort's own denominator and numerator.
  - population: Pooled literature series of 84 reported Nager and Rodriguez patients
    case_fraction_percent: 76.0
    cohort_size: 84
    notes: >-
      Higher than the discovery cohort, drawn from 24 articles and including 9
      Rodriguez syndrome patients, so ascertainment differs from a consecutive
      clinical series.
    evidence:
    - reference: PMID:35331022
      reference_title: "SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients were examined, of which 76% were caused by variants in SF3B4"
      explanation: >-
        Pooled literature estimate of the SF3B4-explained share. The quote is
        trimmed of the bracketed Rodriguez-syndrome aside so it matches the
        cached text; the 84-patient denominator it names is recorded in
        cohort_size.
  evidence:
  - reference: PMID:22541558
    reference_title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome"
    explanation: The gene discovery establishing SF3B4 as the causative gene.
diagnosis:
- name: Molecular genetic testing of SF3B4
  description: >-
    Sequencing of SF3B4 confirms the diagnosis in roughly 60% of clinically
    diagnosed individuals; a negative result does not exclude Nager syndrome,
    since 40% of cases have no identified cause.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The remaining 40% of cases are of unknown cause."
    explanation: States the diagnostic yield limit that this recommendation turns on.
- name: Clinical recognition of the acrofacial pattern
  description: >-
    The diagnosis is made clinically from the combination of mandibulofacial
    dysostosis with preaxial upper-limb anomalies. It is the limb component that
    separates Nager syndrome from the mandibulofacial dysostoses it otherwise
    resembles, so a thumb and forearm examination is part of the craniofacial
    assessment rather than an add-on.
  evidence:
  - reference: PMID:41667381
    reference_title: "Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies."
    explanation: States the two-part clinical pattern the diagnosis rests on.
  - reference: PMID:35331022
    reference_title: "SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies."
    explanation: Independently states the same craniofacial-plus-preaxial-limb definition.
differential_diagnoses:
- name: Treacher Collins syndrome
  description: >-
    Shares the mandibulofacial dysostosis pattern but lacks preaxial limb
    involvement; the thumb and radial defects are what make Nager syndrome
    acrofacial. Neonatal courses also differ — tracheostomy and mortality rates
    are substantially higher in Nager syndrome.
  evidence:
  - reference: PMID:40280475
    reference_title: "Management and Outcomes of Neonates with Treacher Collins and Nager Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."
    explanation: Quantifies the neonatal difference between the two syndromes in a shared cohort.
- name: Rodriguez syndrome
  description: >-
    Also caused by SF3B4 variants, with the same craniofacial pattern but more
    severe, and additionally involving the lower limbs, heart and forebrain.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rodriguez syndrome (OMIM #201170) is another condition due to mutations in SF3B4"
    explanation: Establishes the shared gene that makes this the closest allelic differential.
treatments:
- name: Neonatal airway stabilization and tracheostomy
  description: >-
    Securing the airway is the first priority. Intubation is difficult because
    trismus restricts mouth opening, and a majority of affected neonates
    ultimately require tracheostomy.
  treatment_term:
    preferred_term: tracheotomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:40280475
    reference_title: "Management and Outcomes of Neonates with Treacher Collins and Nager Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with NS had the highest rate of intubation at birth (91%) and tracheostomy placement (72.7%), and a higher mortality rate than TCS (27.3% vs 1.9%)."
    explanation: Quantifies how often airway intervention is needed in this population.
  - reference: PMID:18947886
    reference_title: "Airway management in Nager Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A case of a Nager Syndrome mother delivering a similarly afflicted fetus is presented, with approaches to maintaining both tenuous airways described."
    explanation: >-
      Airway management is the subject of this report; it is a single family, so
      it supports the practice rather than establishing an approach.
- name: Gastrostomy feeding support
  description: >-
    Micrognathia, restricted mouth opening and a secured airway together impair
    oral feeding, and enteral access is commonly needed in the mandibulofacial
    dysostosis population.
  treatment_term:
    preferred_term: gastrostomy tube placement
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:40280475
    reference_title: "Management and Outcomes of Neonates with Treacher Collins and Nager Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with infants with micrognathia, those with TCS were more likely to undergo tracheostomy (54% vs 11%) and gastrostomy tube placement (67% vs 35%)"
    explanation: >-
      The reported gastrostomy rate is for the Treacher Collins arm of the same
      cohort, not the Nager arm, so this supports the practice in
      mandibulofacial dysostosis generally rather than quantifying it in Nager
      syndrome.
- name: Genetic counseling
  description: >-
    Counseling covers de novo occurrence in most cases, autosomal dominant
    transmission from an affected parent, and the 40% of clinically diagnosed
    individuals in whom no causative variant is found.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most cases are sporadic, and both autosomal-dominant and autosomal-recessive inheritances have been reported"
    explanation: The inheritance picture that counseling has to convey.
animal_models:
- name: Xenopus tropicalis sf3b4 CRISPR mutant line
  species: Xenopus tropicalis
  genotype: CRISPR/Cas9-generated sf3b4 deletion, heterozygous and homozygous null, with wild-type siblings
  category: Germline gene-edited mutant line
  publication: PMID:40126363
  description: >-
    A stable frog mutant line built to ask why a ubiquitous splicing factor
    produces a lineage-restricted disease. Its answer has two parts: the splicing
    lesion appears first as excess exon skipping and only later as broad
    transcriptional dysregulation, and the cellular failure is in cranial neural
    crest migration and survival rather than in crest induction. The line also
    delivers the field's clearest human-model mismatch — heterozygous frogs are
    indistinguishable from wild type and form normal craniofacial cartilage,
    while the corresponding human genotype is the disease.
  genes:
  - preferred_term: SF3B4
    term:
      id: hgnc:10771
      label: SF3B4
  modeled_mechanisms:
  - target: Aberrant Pre-mRNA Splicing and Exon Skipping
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Temporal RNA-seq of mutant embryos resolves the splicing lesion into an
      early exon-skipping phase and a later transcriptional collapse, which is
      the ordering this node asserts.
    limitations: >-
      The splicing phenotype is reported for null embryos; heterozygotes differ
      only minimally from wild type at the transcriptome level, so the model
      characterizes what total loss of Sf3b4 does to splicing rather than what
      the patient's half dose does.
    readouts:
    - name: Genes with atypical skipped exons in mutant embryos
      target: Aberrant Pre-mRNA Splicing and Exon Skipping
      direction: INCREASED
      interpretation: >-
        Exon skipping rises before general gene dysregulation, identifying it as
        the primary molecular consequence rather than a downstream effect.
      evidence:
      - reference: PMID:40126363
        reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Temporal RNA-sequencing analyses of mutant embryos identified an increase in exon-skipping events, followed by important transcriptional changes associated with an enrichment for terms consistent with defects in NC cell migration and survival."
        explanation: Reports both the measured increase and its temporal precedence.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we generated a Xenopus tropicalis sf3b4 mutant line using CRISPR/Cas9 gene-editing technology"
      explanation: Establishes the model as a germline edit of the disease gene rather than a transient knockdown.
  - target: Cranial Neural Crest Migration Failure and Apoptosis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Separates induction from migration: pre-migratory crest markers are normal,
      and the phenotype emerges at the migratory stage as shortened crest streams
      with increased head apoptosis.
    limitations: >-
      Severity is dose-dependent and the informative phenotype is largely in the
      null, which is not the human genotype. The apoptotic component is scored by
      TUNEL in the whole head region rather than in identified crest cells, so
      apoptosis of crest cells specifically is inferred.
    readouts:
    - name: Cranial neural crest stream length (sox9, sox10)
      target: Cranial Neural Crest Migration Failure and Apoptosis
      direction: DECREASED
      interpretation: >-
        Shorter streams at the migratory stage, with normal pre-migratory
        markers, place the defect in migration rather than specification.
      evidence:
      - reference: PMID:40126363
        reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Quantification of the phenotype showed a statistically significant reduction of the NC stream length (streams 2 and 3 for sox10, and streams 3 and 4 for sox9) in Het and Null embryos compared to WT siblings"
        explanation: The quantified migration readout.
    - name: TUNEL-positive cells in the head region
      target: Cranial Neural Crest Migration Failure and Apoptosis
      direction: INCREASED
      interpretation: >-
        Cell death rises only once migration begins, matching the stage at which
        the migration defect appears.
      evidence:
      - reference: PMID:40126363
        reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "at the migratory stage (NF stage 25), there was a significant increase in apoptosis in the head region of Het and Null embryos, with a greater number of TUNEL-positive cells in the Null compared to the Het animals"
        explanation: The quantified survival readout and its stage dependence.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that in the absence of Sf3b4 function NC induction is not affected."
      explanation: The control result that makes the migration interpretation possible.
  - target: First and Second Branchial Arch Skeletal Hypoplasia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Null embryos lose the neural-crest-derived cartilage progenitor pool that
      builds the arch skeleton, giving a developmental account of the craniofacial
      hypoplasia.
    limitations: >-
      Null animals die before the tadpole stage, so the mature craniofacial
      skeleton cannot be scored in the genotype that shows the phenotype; and
      the genotype that survives, the heterozygote, forms normal cartilage. The
      readouts are larval frog cartilages, which do not map one-to-one onto the
      human mandible, malar complex and ossicles.
    readouts:
    - name: Craniofacial cartilage formation in heterozygous tadpoles
      target: First and Second Branchial Arch Skeletal Hypoplasia
      direction: UNCHANGED
      interpretation: >-
        A negative result, and the crux of the model's limitation: the genotype
        that corresponds to the human disease produces no craniofacial phenotype
        in the frog.
      evidence:
      - reference: PMID:40126363
        reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "sf3b4 Null animals failed to survive beyond the tadpole stage, but Het tadpoles were indistinguishable from their WT siblings, forming largely normal craniofacial cartilages."
        explanation: Records both the null lethality and the absence of a heterozygous phenotype.
    evidence:
    - reference: PMID:40126363
      reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous deletion of sf3b4 is detrimental to the development of cranial neural crest (NC)-derived cartilage progenitors."
      explanation: Supports the model reporting on the cartilage progenitor pool behind this node.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that disruption of these processes may underly the pathogenesis of Nager and Rodriguez syndromes."
    explanation: >-
      The authors offer the link to human pathogenesis as a proposal, which is
      the level of claim this model supports.
discussions:
- discussion_id: nager_sf3b4_dose_species_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does heterozygous loss of sf3b4 cause no craniofacial phenotype in
    Xenopus tropicalis when the same half dose of SF3B4 causes Nager syndrome in
    humans, and what does that imply for using the frog null as a model of a
    human haploinsufficiency disorder?
  attaches_to:
  - pathophysiology#SF3B4 Haploinsufficiency
  - animal_models#Xenopus tropicalis sf3b4 CRISPR mutant line
  rationale: >-
    Human Nager syndrome is a dominant haploinsufficiency: one truncating SF3B4
    allele is enough. In the frog, heterozygotes are transcriptionally and
    morphologically near-normal and only homozygous nulls show the crest and
    cartilage phenotype — which the authors themselves read as an autosomal
    recessive mode in X. tropicalis. So the genotype that models the disease
    biochemically is not the genotype that models it clinically. Either the frog
    tolerates a lower dose of Sf3b4 than humans do, or something outside gene
    dosage — a modifier, a threshold effect, or a difference in how long cranial
    crest is exposed to the deficit — sets the human threshold. Until that is
    resolved, mechanisms read off the null should be treated as showing what
    losing Sf3b4 can do, not as showing what patients' cells are doing. The
    same question sits underneath the disease's central puzzle, which is why a
    core spliceosome component fails in one lineage only.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our data indicate that sf3b4 haploinsufficiency is compatible with normal development in X. tropicalis, whereas homozygous deletion of sf3b4 is detrimental to survival and the formation of NC-derived cartilage progenitors, consistent with an autosomal recessive mode of inheritance"
    explanation: States the species difference in dose sensitivity in the authors' own terms.
  - reference: PMID:22541558
    reference_title: "Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4."
    explanation: The human side of the mismatch — one allele is sufficient to cause disease in people.
- discussion_id: nager_spliceosome_lineage_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does reduced dose of a ubiquitously required core spliceosome component
    damage cranial neural crest specifically, rather than every dividing tissue?
  attaches_to:
  - pathophysiology#Aberrant Pre-mRNA Splicing and Exon Skipping
  rationale: >-
    This is the defining unanswered question of the spliceosomopathies, and
    nothing in this entry's pathophysiology answers it — the chain from reduced
    SF3B4 to shortened crest streams describes what happens without explaining
    why the crest is where it happens. Candidate explanations include an
    unusually high transcriptional demand in migrating crest, particular
    sensitivity of specific transcripts to branch-point recognition, and a
    p53-linked apoptotic threshold that crest cells cross first. The frog line
    gives the tools to test these, since it separates the splicing change in time
    from the cellular failure.
  evidence:
  - reference: PMID:40126363
    reference_title: "Deletion of sf3b4 causes splicing defects and gene dysregulation that disrupt craniofacial development and survival."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is especially puzzling that variants of a core component of this largely ubiquitous cellular machinery result in such an exquisitely cell type- and lineage-specific defect."
    explanation: States the gap in the authors' own words.
notes: >-
  No GeneReviews chapter exists for Nager syndrome, SF3B4, or acrofacial
  dysostosis — PubMed returns nothing for any of those against the GeneReviews
  book, so the usual GeneReviews baseline could not be mined and none is tagged
  in `references`.

  Orphanet (ORPHA:245) was not consumed as a source. Rebuilding
  `references_cache/ORPHA_245.md` needs the bulk XML pinned in
  `data/orphadata/MANIFEST.yaml`, and Orphadata has since replaced that
  snapshot: `just refresh-orphadata` downloads a file whose sha256 no longer
  matches the pin, so the cache cannot be rebuilt reproducibly here. Bumping the
  manifest would regenerate all 8,823 ORPHA cache files, far outside this
  change. Orphanet's HPO table with frequency bands remains the right source for
  per-phenotype frequencies and should replace the values recorded here.

  Phenotype `frequency:` values are read off defining-feature statements
  ("characterized by", "specifically present with") rather than from a
  frequency-annotated source; the exception is neonatal airway obstruction,
  which rests on measured intervention rates in a neonatal cohort.

  Entry created from the curation stub while adding the Xenopus tropicalis sf3b4
  CRISPR model from Disease Models & Mechanisms. Roughly 40% of clinically
  diagnosed Nager syndrome has no identified genetic cause, so this entry's
  pathophysiology describes the SF3B4 route only. Rodriguez syndrome is treated
  as an allelic differential rather than a subtype, since its lower-limb,
  cardiac and forebrain involvement puts it outside the acrofacial pattern this
  entry describes.

📚

References & Deep Research

References

3

PMID:22541558

Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.

No top-level findings curated for this source.

PMID:35331022

SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome.

No top-level findings curated for this source.

PMID:41667381

Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination.

No top-level findings curated for this source.

Nager Acrofacial Dysostosis

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