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Inheritance

1

X-Linked Recessive HP:0001419

X-linked recessive. Hemizygous males are affected; obligate female carriers are generally clinically and radiographically indistinguishable from the general population, though some show phenotypic changes. Note that TRAPPC2 escapes X-inactivation, which is worth knowing when reasoning about carrier expression.

X-linked recessive inheritance

Show evidence (3 references)

PMID:10431248 SUPPORT Human Clinical

"Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people."

States the inheritance mode and the OMIM identifier recorded in external_assertions.

PMID:10431248 SUPPORT Human Clinical

"Obligate female carriers are generally clinically and radiographically indistinguishable from the general population, although some cases have phenotypic changes consistent with expression of the gene defect."

The carrier-expression claim in this block, including the exception the original authors record.

PMID:32471379 SUPPORT Human Clinical

"A pedigree analysis of 5 generations with 6 affected males revealed an X-linked recessive mode of inheritance."

Independent confirmation of the inheritance mode in a large modern pedigree.

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Discussions and Knowledge Gaps

2

Why is a defect in a ubiquitous TRAPP subunit confined to the skeleton?

KNOWLEDGE GAP sedt_tissue_restriction_of_a_housekeeping_defect

Attached to

pathophysiology#Impaired Sar1 Cycling and COPII Megacarrier Formation pathophysiology#Defective Growth Plate Chondrogenesis

Sedlin is the Trs20 adaptor required for assembly of TRAPP II and TRAPP III, and TRAPP serves general secretion and autophagy in every cell. A complete loss of that function should not produce a skeleton-restricted, late-onset, otherwise-normal phenotype. The standard explanation is cargo-specific: only procollagen needs megacarriers, so only cells with an exceptional procollagen export load fail. That explanation is plausible and fits the data, but it has not been tested against the alternative that residual TRAPP function suffices elsewhere, and no tissue-specific conditional model has been reported. Whether autophagy is measurably affected in SEDT patient cells is, as far as the sources here go, unasked.

Proposed experiments

Autophagic flux in TRAPPC2-null patient cells

sedt_autophagy_in_patient_cells

Measure autophagic flux in patient fibroblasts or chondrocytes against controls, to test whether the TRAPP III arm is functionally spared or merely clinically silent.

Readouts

Autophagic flux

pathophysiology#Absent or Misfolded Sedlin

Direction: UNCHANGED

Interpretation: Unchanged flux would support cargo-specific vulnerability; reduced flux would mean the tissue restriction needs a different explanation.

Show evidence (1 reference)

PMID:27066478 SUPPORT Other

"Another small subunit, Trs20/Sedlin, is an adaptor required for the association of core TRAPP with larger subunits to form TRAPP II and TRAPP III."

Establishes that sedlin's role is general TRAPP assembly rather than anything chondrocyte-specific, which is what makes the tissue restriction a puzzle.

Does the D47Y allele cause SEDT by the same route as the null alleles?

KNOWLEDGE GAP sedt_d47y_distinct_mechanism

Attached to

pathophysiology#Absent or Misfolded Sedlin

Every other characterised allele removes sedlin, by truncation, splicing or proteasomal degradation. D47Y is expressed at wild-type levels and folds normally; what changes is its affinity for Bet3. If it causes the same disease, then altered TRAPP dynamics is sufficient, and the entry's single loss-of-function chain is an oversimplification for at least one allele. The pathophysiology nodes here are written for the loss-of-function majority and this allele is flagged rather than modelled separately, since no D47Y-specific procollagen-export experiment has been reported.

Show evidence (1 reference)

PMID:19650763 SUPPORT In Vitro

"Two independent assays showed that the D47Y mutation resulted in an increased affinity for the transport protein particle component Bet3 compared with the wild-type sedlin."

The measurement that separates D47Y from the degradation mechanism.

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Pathophysiology

6

TRAPPC2 Loss of Function

Hemizygous loss-of-function variants in TRAPPC2 at Xp22. The reported spectrum includes frameshifting dinucleotide deletions, splice-donor variants that skip the exon carrying the start codon, and destabilising missense substitutions. The common endpoint is absence of functional sedlin.

Genetic context TRAPPC2 hgnc:23068 zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Absent or Misfolded Sedlin Null and splice alleles abolish the protein; destabilising missense alleles are degraded.

Show evidence (2 references)

PMID:10431248 SUPPORT Human Clinical

"In one candidate gene we detected three dinucleotide deletions in three Australian families which effect frameshifts causing premature stop codons."

The gene-identifying observation: frameshifting deletions in three families, establishing loss of function as the mechanism.

PMID:11326333 SUPPORT Human Clinical

"Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame."

A second loss-of-function route, demonstrated at the transcript level rather than inferred from the DNA change.

Absent or Misfolded Sedlin

Two distinct routes to the same endpoint. Truncating and splice alleles produce no protein. The missense substitutions S73L, F83S and V130D misfold and are degraded by the proteasome, which is why proteasome inhibition restores their expression. D47Y is the exception that proves the rule: it folds normally and is expressed, but binds the TRAPP subunit Bet3 with altered affinity, so it disrupts TRAPP dynamics rather than protein abundance.

Chondrocyte CL:0000138

Downstream

Impaired Sar1 Cycling and COPII Megacarrier Formation Sedlin is the subunit that promotes Sar1 cycling at ER exit sites.

Show evidence (3 references)

PMID:19650763 SUPPORT In Vitro

"The D47Y mutant was expressed similarly to the wild-type, but the S73L, F83S and V130D mutants showed particularly low levels of expression that were rescued in the presence of the proteasome inhibitor MG132 (benzyloxycarbonyl-leucylleucylleucinal)."

Demonstrates proteasomal degradation of the destabilising mutants, with the MG132 rescue that makes the interpretation causal.

PMID:19650763 SUPPORT In Vitro

"Our results suggest that the sedlin mutations S73L, F83S and V130D cause SEDT by sedlin misfolding, whereas the D47Y mutation may influence normal TRAPP (transport protein particle) dynamics."

States both routes to loss of function, including the non-degradative one.

PMID:19650763 SUPPORT INDIRECT Model Organism

"In situ hybridization and immunohistochemical experiments in mouse growth plates revealed sedlin to be predominantly expressed in proliferating and hypertrophic chondrocytes."

Localises sedlin to the exact cells where the disease manifests. Indirect because the expression data are from mouse growth plate, not human.

Impaired Sar1 Cycling and COPII Megacarrier Formation

TANGO1 recruits sedlin to ER exit sites; sedlin binds Sar1 and promotes its efficient cycling. Sar1 is the GTPase whose membrane constriction limits carrier size, so efficient cycling is what lets a nascent COPII carrier keep growing into a megacarrier. Without sedlin, carriers cannot enlarge.

COPII-coated vesicle cargo loading GO:0090110 ↓ DECREASED

Downstream

Procollagen Retention in Dilated Rough Endoplasmic Reticulum Procollagen prefibrils that cannot be packaged accumulate in the ER lumen.

Show evidence (2 references)

PMID:23019651 SUPPORT In Vitro

"Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils."

The central molecular result: sedlin acts on Sar1, and the consequence is carrier growth sufficient for procollagen.

PMID:23019651 SUPPORT In Vitro

"We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC."

Establishes the recruitment step and that sedlin is required for procollagen export, naming SEDT explicitly as the disease context.

Procollagen Retention in Dilated Rough Endoplasmic Reticulum

The morphological signature of the secretory bottleneck. Articular cartilage from an affected adult contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum. This is the one step in the chain observed directly in human tissue rather than in a cell line.

Chondrocyte CL:0000138

endoplasmic reticulum to Golgi vesicle-mediated transport GO:0006888 ↓ DECREASED

Downstream

Defective Growth Plate Chondrogenesis Reduced delivery of collagen matrix impairs endochondral ossification.

Show evidence (2 references)

PMID:11326333 SUPPORT Human Clinical

"Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER)."

The human-tissue ultrastructural observation this node records.

PMID:11326333 SUPPORT INDIRECT Human Clinical

"These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis."

The authors' own interpretation, offered as a suggestion. Recorded indirect because in 2001 the pathway was inferred from yeast homology; the procollagen mechanism was not demonstrated until 2012.

Defective Growth Plate Chondrogenesis

Impaired matrix secretion at the vertebral and epiphyseal growth plates. Because it is a defect of growth rather than of a formed structure, nothing is visible at birth and the phenotype only emerges after years of growth, which is what "tarda" records.

Chondrocyte CL:0000138

Downstream

Platyspondyly

Disproportionate short-trunk short stature

Epiphyseal dysplasia

Barrel-shaped chest

Altered Spinal and Hip Joint Biomechanics

Show evidence (1 reference)

PMID:23019651 SUPPORT INDIRECT In Vitro

"This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT."

The link from the trafficking defect to chondrogenesis. Graded INDIRECT and quoted with the authors' "may explain": the chondrogenesis step is an inference from the trafficking result, not a measurement in growth-plate tissue.

Altered Spinal and Hip Joint Biomechanics

Malformed vertebral bodies and dysplastic, narrow hip joints load abnormally and wear early. The osteoarthritis of SEDT is therefore secondary and mechanical, not a primary cartilage-degradation disease, which is why joint replacement works so well.

Downstream

Osteoarthritis

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."

States that the epiphyseal dysplasia leads to secondary osteoarthritis, which is exactly the causal claim this node makes.

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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

6

Musculoskeletal 4

Platyspondyly HP:0000926

Show evidence (2 references)

PMID:10431248 SUPPORT Human Clinical

"Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia."

Describes the platyspondyly and its distinctive hump-shaped form.

PMID:32471379 SUPPORT Human Clinical

"His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis."

Independent confirmation of the same radiographic sign in a modern case.

Barrel-shaped chest HP:0001552

Show evidence (1 reference)

PMID:11760838 SUPPORT Human Clinical

"Spondyloepiphyseal dysplasia tarda (SEDT), an X-linked recessive skeletal disorder, presents with disproportionate short stature and "barrel-chest" deformity in affected (hemizygous) adolescent boys."

States the barrel-chest deformity as a presenting feature, and its restriction to hemizygous boys.

Epiphyseal dysplasia HP:0002656

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia."

Reports the epiphyseal dysplasia and grades it mild to moderate.

Osteoarthritis HP:0002758

Onset: YOUNG ADULT

Show evidence (2 references)

PMID:10431248 SUPPORT Human Clinical

"The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."

States the premature secondary osteoarthritis and its usual consequence.

PMID:32471379 SUPPORT Human Clinical

"It is clinically characterized by disproportionate short stature and early onset of degenerative osteoarthritis."

Independent statement of early-onset degenerative osteoarthritis as a defining feature.

Growth 1

Disproportionate short-trunk short stature HP:0003521

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."

States the short-trunk short stature and, importantly for this entry, the absence of systemic complications.

Other 1

Flattened femoral head HP:0008812

Show evidence (1 reference)

PMID:32471379 SUPPORT Human Clinical

"the radiograph of the hips showed flattened femoral heads, narrow hip-joint surfaces, and osteosclerosis of the pelvis"

Direct radiographic report of the flattened femoral heads in the proband.

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Genetic Associations

1

TRAPPC2

Gene: TRAPPC2 hgnc:23068 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:10431248 SUPPORT Human Clinical

"The gene designated SEDL is transcribed as a 2.8-kb transcript in many tissues including fetal cartilage."

Gives the transcript size and the expression pattern, including fetal cartilage.

PMID:10431248 SUPPORT Human Clinical

"SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport."

The protein size and the trafficking role, proposed here and demonstrated thirteen years later.

PMID:11326333 SUPPORT Human Clinical

"RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation."

Supports the X-inactivation-escape claim in these notes.

+ 1 more reference

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External Assertions

1

OMIM X-linked spondyloepiphyseal dysplasia tarda record

OMIM disease record OMIM:313400

OMIM phenotype identifier, cited as MIM 313400 in PMID:10431248.

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Medical Actions

2

Hip Arthroplasty for End-Stage Hip Osteoarthritis

Action: hip replacement Ontology label: Hip Replacement NCIT:C157876

Platform: Surgery

Joint replacement for the secondary osteoarthritis. Because the arthritis is mechanical rather than a primary cartilage disease, replacing the joint addresses the actual problem, and it is the only intervention in this entry that changes the natural history of a manifestation.

Mechanism Target:

Altered Spinal and Hip Joint Biomechanics — Replaces the dysplastic articulation whose abnormal loading drives the degeneration.

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."

Establishes hip arthroplasty as the usual endpoint of management in this disease.

Molecular Carrier Testing and Presymptomatic Diagnosis

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

Platform: Other

Once the familial TRAPPC2 variant is known, testing identifies carriers and diagnoses affected boys before any clinical or radiographic sign appears. The clinical value of pre-expression diagnosis is not established: the authors who demonstrated it propose joint protection as a possible benefit but explicitly frame it as unproven.

Show evidence (2 references)

PMID:11760838 SUPPORT Human Clinical

"Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT."

Establishes that presymptomatic molecular diagnosis is possible, which is what this entry claims.

PMID:11760838 SUPPORT INDIRECT Human Clinical

"Although there is no specific treatment for SEDT, preexpression molecular testing of SEDL could be helpful if avoiding physical activities potentially injurious to the spine and the joints proves beneficial."

The benefit claim, quoted with its two conditionals intact. Graded INDIRECT because joint protection has not been shown to alter outcome; the sentence proposes it rather than reporting it.

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Diagnosis

1

Characteristic radiographs with normal metabolic studies, confirmed by TRAPPC2 sequencing

The diagnosis is radiographic plus molecular. The finding that does the most diagnostic work is a negative one: metabolic laboratory studies are normal, which is what separates SEDT from the mucopolysaccharidoses it can resemble on film. Clinical diagnosis is nonetheless often delayed, precisely because nothing is abnormal until late childhood and no metabolic screen flags it.

Show evidence (3 references)

PMID:32471379 SUPPORT Human Clinical

"Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites."

States both the diagnostic difficulty and its cause. The source spells "abnomalites"; the snippet reproduces the source rather than correcting it.

PMID:32471379 SUPPORT Human Clinical

"Genetic diagnosis is critical in both early diagnosis and management of the disease."

States the role of molecular confirmation.

PMID:10431248 SUPPORT Human Clinical

"This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."

The "absence of systemic complications" is the discriminating negative this diagnostic entry rests on.

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Prevalence

1

Worldwide

Point Prevalence 0.2 per 100,000 1–9 per 1,000,000

Approximately two per million, as stated in the gene-identification paper. The figure is asserted rather than derived from a cited epidemiological study, and it is not sex-stratified even though the disease affects hemizygous males.

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people."

The source of the two-per-million figure this record normalises.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from X-Linked Spondyloepiphyseal Dysplasia Tarda:

Mucopolysaccharidoses

Overlapping Features Radiographically similar dysostosis, separated by the systemic and biochemical findings that SEDT lacks: normal metabolic studies and no abnormal urinary glycosaminoglycan excretion.

Show evidence (1 reference)

PMID:10431248 SUPPORT Human Clinical

"This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."

The absence of systemic complications is the discriminator against the storage disorders.

Autosomal spondyloepiphyseal dysplasia tarda

Overlapping Features SEDT is genetically heterogeneous and both autosomal and X-linked forms are described; only the X-linked form is TRAPPC2-related and only it is this entry. Pedigree structure, not radiography, separates them.

Show evidence (1 reference)

PMID:11326333 SUPPORT Human Clinical

"Both autosomal and X-linked forms have been described."

States the genetic heterogeneity that makes this differential necessary.

Spondyloepiphyseal dysplasia congenita (COL2A1)

Overlapping Features Present at birth with more severe short stature and frequent ocular involvement, where SEDT is normal at birth and skeleton-restricted.

Progressive pseudorheumatoid dysplasia (CCN6/WISP3)

Overlapping Features Also presents in childhood with platyspondyly and progressive joint disease, but is autosomal recessive and affects both sexes.

{ }

Source YAML

click to show

name: X-Linked Spondyloepiphyseal Dysplasia Tarda
creation_date: "2026-09-06T19:15:00Z"
category: Mendelian
description: >-
  X-linked spondyloepiphyseal dysplasia tarda (SEDT) is a late-onset X-linked
  recessive osteochondrodysplasia caused by loss-of-function variants in
  TRAPPC2 (formerly SEDL), which encodes the 140-amino-acid protein sedlin, the
  Trs20 adaptor subunit of the TRAPP tethering complex.

  The mechanism is unusually satisfying for a skeletal dysplasia because it
  explains the tissue restriction. Sedlin binds Sar1 and promotes its GTPase
  cycling at endoplasmic reticulum exit sites, which is what allows COPII
  carriers to enlarge into the megacarriers needed to export procollagen
  prefibrils. Procollagen is simply too bulky for a standard COPII vesicle. Any
  cell that secretes ordinary cargo can manage without sedlin; a growth-plate
  chondrocyte, whose whole job is exporting collagen, cannot. Patient articular
  cartilage shows the predicted secretory bottleneck as dilated rough
  endoplasmic reticulum.

  Affected hemizygous males are normal at birth and present in late childhood
  or adolescence with disproportionate short-trunk short stature, a barrel
  chest and the near-pathognomonic hump-shaped platyspondyly, followed by
  premature osteoarthritis of spine and hips. Because the lesion is confined to
  the skeleton, metabolic laboratory values are normal, which is the finding
  that separates SEDT from the mucopolysaccharidoses it can resemble
  radiographically. Life expectancy is normal. There is no disease-modifying
  therapy; management is orthopaedic, and hip arthroplasty is the definitive
  treatment for end-stage hip disease.
disease_term:
  preferred_term: spondyloepiphyseal dysplasia tarda, X-linked
  term:
    id: MONDO:0010737
    label: spondyloepiphyseal dysplasia tarda, X-linked
synonyms:
- SEDT
- SEDL
- spondyloepiphyseal dysplasia late
- X-linked spondyloepiphyseal dysplasia tarda
- TRAPPC2-related spondyloepiphyseal dysplasia
parents:
- Spondyloepiphyseal Dysplasia
external_assertions:
- name: OMIM X-linked spondyloepiphyseal dysplasia tarda record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:313400
  description: >-
    OMIM phenotype identifier, cited as MIM 313400 in PMID:10431248.
references:
- reference: PMID:10431248
  title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
  findings: []
- reference: PMID:23019651
  title: "Sedlin controls the ER export of procollagen by regulating the Sar1 cycle."
  findings: []
- reference: PMID:11326333
  title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
  findings: []
- reference: PMID:19650763
  title: "Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda."
  findings: []
- reference: PMID:11760838
  title: "Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin."
  findings: []
- reference: PMID:32471379
  title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
  findings: []
- reference: PMID:27066478
  title: "TRAPP Complexes in Secretion and Autophagy."
  findings: []
inheritance:
- name: X-Linked Recessive
  description: >-
    X-linked recessive. Hemizygous males are affected; obligate female carriers
    are generally clinically and radiographically indistinguishable from the
    general population, though some show phenotypic changes. Note that TRAPPC2
    escapes X-inactivation, which is worth knowing when reasoning about carrier
    expression.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people."
    explanation: >-
      States the inheritance mode and the OMIM identifier recorded in
      external_assertions.
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Obligate female carriers are generally clinically and radiographically indistinguishable from the general population, although some cases have phenotypic changes consistent with expression of the gene defect."
    explanation: >-
      The carrier-expression claim in this block, including the exception the
      original authors record.
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A pedigree analysis of 5 generations with 6 affected males revealed an X-linked recessive mode of inheritance."
    explanation: >-
      Independent confirmation of the inheritance mode in a large modern
      pedigree.
pathophysiology:
- name: TRAPPC2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Hemizygous loss-of-function variants in TRAPPC2 at Xp22. The reported
    spectrum includes frameshifting dinucleotide deletions, splice-donor
    variants that skip the exon carrying the start codon, and destabilising
    missense substitutions. The common endpoint is absence of functional
    sedlin.
  genetic_context:
    gene:
      preferred_term: TRAPPC2
      term:
        id: hgnc:23068
        label: TRAPPC2
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one candidate gene we detected three dinucleotide deletions in three Australian families which effect frameshifts causing premature stop codons."
    explanation: >-
      The gene-identifying observation: frameshifting deletions in three
      families, establishing loss of function as the mechanism.
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame."
    explanation: >-
      A second loss-of-function route, demonstrated at the transcript level
      rather than inferred from the DNA change.
  downstream:
  - target: Absent or Misfolded Sedlin
    description: >-
      Null and splice alleles abolish the protein; destabilising missense
      alleles are degraded.
- name: Absent or Misfolded Sedlin
  biological_scale: MOLECULAR
  description: >-
    Two distinct routes to the same endpoint. Truncating and splice alleles
    produce no protein. The missense substitutions S73L, F83S and V130D misfold
    and are degraded by the proteasome, which is why proteasome inhibition
    restores their expression. D47Y is the exception that proves the rule: it
    folds normally and is expressed, but binds the TRAPP subunit Bet3 with
    altered affinity, so it disrupts TRAPP dynamics rather than protein
    abundance.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:19650763
    reference_title: "Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The D47Y mutant was expressed similarly to the wild-type, but the S73L, F83S and V130D mutants showed particularly low levels of expression that were rescued in the presence of the proteasome inhibitor MG132 (benzyloxycarbonyl-leucylleucylleucinal)."
    explanation: >-
      Demonstrates proteasomal degradation of the destabilising mutants, with
      the MG132 rescue that makes the interpretation causal.
  - reference: PMID:19650763
    reference_title: "Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results suggest that the sedlin mutations S73L, F83S and V130D cause SEDT by sedlin misfolding, whereas the D47Y mutation may influence normal TRAPP (transport protein particle) dynamics."
    explanation: >-
      States both routes to loss of function, including the non-degradative one.
  - reference: PMID:19650763
    reference_title: "Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In situ hybridization and immunohistochemical experiments in mouse growth plates revealed sedlin to be predominantly expressed in proliferating and hypertrophic chondrocytes."
    explanation: >-
      Localises sedlin to the exact cells where the disease manifests. Indirect
      because the expression data are from mouse growth plate, not human.
  downstream:
  - target: Impaired Sar1 Cycling and COPII Megacarrier Formation
    description: >-
      Sedlin is the subunit that promotes Sar1 cycling at ER exit sites.
- name: Impaired Sar1 Cycling and COPII Megacarrier Formation
  biological_scale: MOLECULAR
  description: >-
    TANGO1 recruits sedlin to ER exit sites; sedlin binds Sar1 and promotes its
    efficient cycling. Sar1 is the GTPase whose membrane constriction limits
    carrier size, so efficient cycling is what lets a nascent COPII carrier
    keep growing into a megacarrier. Without sedlin, carriers cannot enlarge.
  biological_processes:
  - preferred_term: COPII-coated vesicle cargo loading
    term:
      id: GO:0090110
      label: COPII-coated vesicle cargo loading
    modifier: DECREASED
  evidence:
  - reference: PMID:23019651
    reference_title: "Sedlin controls the ER export of procollagen by regulating the Sar1 cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils."
    explanation: >-
      The central molecular result: sedlin acts on Sar1, and the consequence is
      carrier growth sufficient for procollagen.
  - reference: PMID:23019651
    reference_title: "Sedlin controls the ER export of procollagen by regulating the Sar1 cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC."
    explanation: >-
      Establishes the recruitment step and that sedlin is required for
      procollagen export, naming SEDT explicitly as the disease context.
  downstream:
  - target: Procollagen Retention in Dilated Rough Endoplasmic Reticulum
    description: >-
      Procollagen prefibrils that cannot be packaged accumulate in the ER
      lumen.
- name: Procollagen Retention in Dilated Rough Endoplasmic Reticulum
  biological_scale: CELLULAR
  description: >-
    The morphological signature of the secretory bottleneck. Articular
    cartilage from an affected adult contained chondrocytes with abundant Golgi
    complexes and dilated rough endoplasmic reticulum. This is the one step in
    the chain observed directly in human tissue rather than in a cell line.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: endoplasmic reticulum to Golgi vesicle-mediated transport
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
    modifier: DECREASED
  evidence:
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER)."
    explanation: >-
      The human-tissue ultrastructural observation this node records.
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis."
    explanation: >-
      The authors' own interpretation, offered as a suggestion. Recorded
      indirect because in 2001 the pathway was inferred from yeast homology;
      the procollagen mechanism was not demonstrated until 2012.
  downstream:
  - target: Defective Growth Plate Chondrogenesis
    description: >-
      Reduced delivery of collagen matrix impairs endochondral ossification.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Defective Growth Plate Chondrogenesis
  biological_scale: TISSUE
  description: >-
    Impaired matrix secretion at the vertebral and epiphyseal growth plates.
    Because it is a defect of growth rather than of a formed structure, nothing
    is visible at birth and the phenotype only emerges after years of growth,
    which is what "tarda" records.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:23019651
    reference_title: "Sedlin controls the ER export of procollagen by regulating the Sar1 cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT."
    explanation: >-
      The link from the trafficking defect to chondrogenesis. Graded INDIRECT
      and quoted with the authors' "may explain": the chondrogenesis step is an
      inference from the trafficking result, not a measurement in growth-plate
      tissue.
  downstream:
  - target: Platyspondyly
  - target: Disproportionate short-trunk short stature
  - target: Epiphyseal dysplasia
  - target: Barrel-shaped chest
  - target: Altered Spinal and Hip Joint Biomechanics
- name: Altered Spinal and Hip Joint Biomechanics
  biological_scale: ORGANISM
  description: >-
    Malformed vertebral bodies and dysplastic, narrow hip joints load abnormally
    and wear early. The osteoarthritis of SEDT is therefore secondary and
    mechanical, not a primary cartilage-degradation disease, which is why joint
    replacement works so well.
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."
    explanation: >-
      States that the epiphyseal dysplasia leads to secondary osteoarthritis,
      which is exactly the causal claim this node makes.
  downstream:
  - target: Osteoarthritis
phenotypes:
- category: Skeletal
  name: Platyspondyly
  description: >-
    Platyspondyly with hump-shaped central and posterior portions of the
    vertebral bodies. The hump is the near-pathognomonic radiographic sign and
    the reason the diagnosis can often be made from a lateral spine film.
  phenotype_term:
    preferred_term: hump-shaped platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia."
    explanation: >-
      Describes the platyspondyly and its distinctive hump-shaped form.
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis."
    explanation: >-
      Independent confirmation of the same radiographic sign in a modern case.
- category: Skeletal
  name: Disproportionate short-trunk short stature
  description: >-
    Disproportionate short stature with a short neck and trunk, absent at birth
    and emerging in late childhood or adolescence.
  phenotype_term:
    preferred_term: Disproportionate short-trunk short stature
    term:
      id: HP:0003521
      label: Disproportionate short-trunk short stature
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."
    explanation: >-
      States the short-trunk short stature and, importantly for this entry, the
      absence of systemic complications.
- category: Skeletal
  name: Barrel-shaped chest
  phenotype_term:
    preferred_term: Barrel-shaped chest
    term:
      id: HP:0001552
      label: Barrel-shaped chest
  evidence:
  - reference: PMID:11760838
    reference_title: "Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spondyloepiphyseal dysplasia tarda (SEDT), an X-linked recessive skeletal disorder, presents with disproportionate short stature and \"barrel-chest\" deformity in affected (hemizygous) adolescent boys."
    explanation: >-
      States the barrel-chest deformity as a presenting feature, and its
      restriction to hemizygous boys.
- category: Skeletal
  name: Epiphyseal dysplasia
  description: >-
    Graded "mild to moderate" by the source. No `severity` value is set: the
    enum is single-valued, so recording MODERATE would assert the upper bound
    of a range in every patient.
  phenotype_term:
    preferred_term: Epiphyseal dysplasia
    term:
      id: HP:0002656
      label: Epiphyseal dysplasia
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia."
    explanation: >-
      Reports the epiphyseal dysplasia and grades it mild to moderate.
- category: Skeletal
  name: Flattened femoral head
  description: >-
    The hip-side radiographic finding underlying the premature hip
    osteoarthritis and, ultimately, the arthroplasty. Reported alongside narrow
    hip-joint surfaces and pelvic osteosclerosis, neither of which is curated
    here: HPO has no hip-specific narrow-joint-space term and no pelvic
    osteosclerosis term, and binding the elbow or wrist variants, or the
    generic increased-bone-mineral-density term, would misstate the site.
  phenotype_term:
    preferred_term: Flattened femoral head
    term:
      id: HP:0008812
      label: Flattened femoral head
  evidence:
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the radiograph of the hips showed flattened femoral heads, narrow hip-joint surfaces, and osteosclerosis of the pelvis"
    explanation: >-
      Direct radiographic report of the flattened femoral heads in the proband.
- category: Skeletal
  name: Osteoarthritis
  description: >-
    Premature secondary osteoarthritis of the spine and hips, the dominant
    source of disability and the reason most patients come to orthopaedic care.
  phenotype_term:
    preferred_term: premature secondary osteoarthritis of spine and hips
    term:
      id: HP:0002758
      label: Osteoarthritis
    onset:
      onset_category: YOUNG_ADULT
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."
    explanation: >-
      States the premature secondary osteoarthritis and its usual consequence.
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is clinically characterized by disproportionate short stature and early onset of degenerative osteoarthritis."
    explanation: >-
      Independent statement of early-onset degenerative osteoarthritis as a
      defining feature.
genetic:
- name: TRAPPC2
  gene_term:
    preferred_term: TRAPPC2
    term:
      id: hgnc:23068
      label: TRAPPC2
  relationship_type: CAUSATIVE
  notes: >-
    TRAPPC2 (formerly SEDL) is at Xp22, transcribed as a 2.8-kb message in many
    tissues including fetal cartilage, and encodes a 140-amino-acid protein.
    Two features are worth carrying: the gene escapes X-inactivation, and it
    has a transcribed retropseudogene on chromosome 19 that can confound
    sequencing if primers are not chosen to exclude it.
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gene designated SEDL is transcribed as a 2.8-kb transcript in many tissues including fetal cartilage."
    explanation: >-
      Gives the transcript size and the expression pattern, including fetal
      cartilage.
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport."
    explanation: >-
      The protein size and the trafficking role, proposed here and demonstrated
      thirteen years later.
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation."
    explanation: >-
      Supports the X-inactivation-escape claim in these notes.
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae."
    explanation: >-
      Supports the retropseudogene caveat, which matters for assay design.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.2
  rate_denominator: POPULATION
  notes: >-
    Approximately two per million, as stated in the gene-identification paper.
    The figure is asserted rather than derived from a cited epidemiological
    study, and it is not sex-stratified even though the disease affects
    hemizygous males.
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people."
    explanation: >-
      The source of the two-per-million figure this record normalises.
treatments:
- name: Hip Arthroplasty for End-Stage Hip Osteoarthritis
  description: >-
    Joint replacement for the secondary osteoarthritis. Because the arthritis is
    mechanical rather than a primary cartilage disease, replacing the joint
    addresses the actual problem, and it is the only intervention in this entry
    that changes the natural history of a manifestation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hip replacement
    term:
      id: NCIT:C157876
      label: Hip Replacement
  target_mechanisms:
  - target: Altered Spinal and Hip Joint Biomechanics
    description: >-
      Replaces the dysplastic articulation whose abnormal loading drives the
      degeneration.
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty."
    explanation: >-
      Establishes hip arthroplasty as the usual endpoint of management in this
      disease.
- name: Molecular Carrier Testing and Presymptomatic Diagnosis
  description: >-
    Once the familial TRAPPC2 variant is known, testing identifies carriers and
    diagnoses affected boys before any clinical or radiographic sign appears.
    The clinical value of pre-expression diagnosis is not established: the
    authors who demonstrated it propose joint protection as a possible benefit
    but explicitly frame it as unproven.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11760838
    reference_title: "Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT."
    explanation: >-
      Establishes that presymptomatic molecular diagnosis is possible, which is
      what this entry claims.
  - reference: PMID:11760838
    reference_title: "Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Although there is no specific treatment for SEDT, preexpression molecular testing of SEDL could be helpful if avoiding physical activities potentially injurious to the spine and the joints proves beneficial."
    explanation: >-
      The benefit claim, quoted with its two conditionals intact. Graded
      INDIRECT because joint protection has not been shown to alter outcome;
      the sentence proposes it rather than reporting it.
diagnosis:
- name: Characteristic radiographs with normal metabolic studies, confirmed by TRAPPC2 sequencing
  description: >-
    The diagnosis is radiographic plus molecular. The finding that does the most
    diagnostic work is a negative one: metabolic laboratory studies are normal,
    which is what separates SEDT from the mucopolysaccharidoses it can resemble
    on film. Clinical diagnosis is nonetheless often delayed, precisely because
    nothing is abnormal until late childhood and no metabolic screen flags it.
  evidence:
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites."
    explanation: >-
      States both the diagnostic difficulty and its cause. The source spells
      "abnomalites"; the snippet reproduces the source rather than correcting
      it.
  - reference: PMID:32471379
    reference_title: "A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic diagnosis is critical in both early diagnosis and management of the disease."
    explanation: >-
      States the role of molecular confirmation.
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."
    explanation: >-
      The "absence of systemic complications" is the discriminating negative
      this diagnostic entry rests on.
differential_diagnoses:
- name: Mucopolysaccharidoses
  description: >-
    Radiographically similar dysostosis, separated by the systemic and
    biochemical findings that SEDT lacks: normal metabolic studies and no
    abnormal urinary glycosaminoglycan excretion.
  evidence:
  - reference: PMID:10431248
    reference_title: "Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications."
    explanation: >-
      The absence of systemic complications is the discriminator against the
      storage disorders.
- name: Autosomal spondyloepiphyseal dysplasia tarda
  description: >-
    SEDT is genetically heterogeneous and both autosomal and X-linked forms are
    described; only the X-linked form is TRAPPC2-related and only it is this
    entry. Pedigree structure, not radiography, separates them.
  evidence:
  - reference: PMID:11326333
    reference_title: "A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both autosomal and X-linked forms have been described."
    explanation: >-
      States the genetic heterogeneity that makes this differential necessary.
- name: Spondyloepiphyseal dysplasia congenita (COL2A1)
  description: >-
    Present at birth with more severe short stature and frequent ocular
    involvement, where SEDT is normal at birth and skeleton-restricted.
- name: Progressive pseudorheumatoid dysplasia (CCN6/WISP3)
  description: >-
    Also presents in childhood with platyspondyly and progressive joint
    disease, but is autosomal recessive and affects both sexes.
discussions:
- discussion_id: sedt_tissue_restriction_of_a_housekeeping_defect
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired Sar1 Cycling and COPII Megacarrier Formation
  - pathophysiology#Defective Growth Plate Chondrogenesis
  prompt: >-
    Why is a defect in a ubiquitous TRAPP subunit confined to the skeleton?
  rationale: >-
    Sedlin is the Trs20 adaptor required for assembly of TRAPP II and TRAPP
    III, and TRAPP serves general secretion and autophagy in every cell. A
    complete loss of that function should not produce a skeleton-restricted,
    late-onset, otherwise-normal phenotype. The standard explanation is
    cargo-specific: only procollagen needs megacarriers, so only cells with an
    exceptional procollagen export load fail. That explanation is plausible and
    fits the data, but it has not been tested against the alternative that
    residual TRAPP function suffices elsewhere, and no tissue-specific
    conditional model has been reported. Whether autophagy is measurably
    affected in SEDT patient cells is, as far as the sources here go, unasked.
  evidence:
  - reference: PMID:27066478
    reference_title: "TRAPP Complexes in Secretion and Autophagy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Another small subunit, Trs20/Sedlin, is an adaptor required for the association of core TRAPP with larger subunits to form TRAPP II and TRAPP III."
    explanation: >-
      Establishes that sedlin's role is general TRAPP assembly rather than
      anything chondrocyte-specific, which is what makes the tissue
      restriction a puzzle.
  proposed_experiments:
  - experiment_id: sedt_autophagy_in_patient_cells
    name: Autophagic flux in TRAPPC2-null patient cells
    description: >-
      Measure autophagic flux in patient fibroblasts or chondrocytes against
      controls, to test whether the TRAPP III arm is functionally spared or
      merely clinically silent.
    readouts:
    - name: Autophagic flux
      target: pathophysiology#Absent or Misfolded Sedlin
      direction: UNCHANGED
      interpretation: >-
        Unchanged flux would support cargo-specific vulnerability; reduced flux
        would mean the tissue restriction needs a different explanation.
- discussion_id: sedt_d47y_distinct_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Absent or Misfolded Sedlin
  prompt: >-
    Does the D47Y allele cause SEDT by the same route as the null alleles?
  rationale: >-
    Every other characterised allele removes sedlin, by truncation, splicing or
    proteasomal degradation. D47Y is expressed at wild-type levels and folds
    normally; what changes is its affinity for Bet3. If it causes the same
    disease, then altered TRAPP dynamics is sufficient, and the entry's single
    loss-of-function chain is an oversimplification for at least one allele.
    The pathophysiology nodes here are written for the loss-of-function
    majority and this allele is flagged rather than modelled separately, since
    no D47Y-specific procollagen-export experiment has been reported.
  evidence:
  - reference: PMID:19650763
    reference_title: "Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Two independent assays showed that the D47Y mutation resulted in an increased affinity for the transport protein particle component Bet3 compared with the wild-type sedlin."
    explanation: >-
      The measurement that separates D47Y from the degradation mechanism.
notes: >-
  On the deep-research report. An openscientist report was generated for this
  entry and passed the Named Entity Confusion preflight (TRAPPC2 mentioned 21
  times, no rival gene). Every PMID used from it was independently checked
  against PubMed before citation and every one resolved to the paper the report
  named, which is not the usual outcome and is worth recording. One
  transcription difference was found and not carried over: the report writes
  the recurrent splice allele as c.93+5G>A, whereas PMID:11326333 writes
  "IVS3+5G-->A at the intron 3 splice-donor site". This entry quotes the source
  and does not assert the HGVS form.

  Report content deliberately not curated. The report cites PMID:33550353 for
  Harris hip scores after arthroplasty and PMID:23043269 for registry
  durability. Both are about spondyloepiphyseal dysplasia or paediatric hip
  disease in general rather than about SEDT specifically, so the arthroplasty
  treatment here is supported from PMID:10431248 instead and the outcome
  figures are left out. The report also proposes GO:0006914 (autophagy) as an
  annotation marked "inferred"; inferred is not evidence, so it appears in the
  knowledge-gap discussion rather than on a node.

  Not curated, and why. No `datasets:`, `clinical_trials:`, `animal_models:` or
  `computational_models:` - no verified accession, trial registration or
  reported model organism for this disease was found. No `biochemical:` - the
  diagnostically important laboratory fact here is that the tests are normal,
  which is curated as a diagnostic and differential claim rather than as a
  biomarker. `directness` is set on six items only, where it was actually
  assessed.

  On two report phenotypes not carried. The deep-research report lists kyphosis
  (HP:0002808) and scoliosis (HP:0002650) as variable childhood and adolescent
  features. Neither is stated by any reference committed here, so neither is
  curated; they are recorded in this note rather than left as a silent
  omission, and either can be added once a source that states it is fetched.

  On the hip radiographic findings. `Flattened femoral head` (HP:0008812) is
  curated from PMID:32471379. The same sentence reports narrow hip-joint
  surfaces and pelvic osteosclerosis, which are not: HPO has no hip-specific
  narrow-joint-space term (only elbow, wrist and carpal variants) and no pelvic
  osteosclerosis term, and the generic increased-bone-mineral-density term
  would misstate the site.

📚

References & Deep Research

References

7

PMID:10431248

Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda.

No top-level findings curated for this source.

PMID:23019651

Sedlin controls the ER export of procollagen by regulating the Sar1 cycle.

No top-level findings curated for this source.

PMID:11326333

A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda.

No top-level findings curated for this source.

PMID:19650763

Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda.

No top-level findings curated for this source.

PMID:11760838

Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin.

No top-level findings curated for this source.

PMID:32471379

A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family.

No top-level findings curated for this source.

PMID:27066478

TRAPP Complexes in Secretion and Autophagy.

No top-level findings curated for this source.

Deep Research

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X-Linked Spondyloepiphyseal Dysplasia Tarda (SEDT) — Comprehensive Disease Report

openscientist-autonomous 19 citations 2026-09-06T19:26:30.467628

X-Linked Spondyloepiphyseal Dysplasia Tarda (SEDT) — Comprehensive Disease Report

MONDO: MONDO:0010737 · OMIM (phenotype): 313400 · OMIM (gene): 300202 · Gene: TRAPPC2 (SEDL), Xp22.2 · Category: Mendelian, X-linked recessive

Evidence base: This report is compiled from aggregated disease-level resources (OMIM, Orphanet) and primary human genetic/clinical literature (case series, pedigrees, molecular studies) plus in vitro / cell-biology mechanistic studies. There are no population EHR datasets or omics data files for this ultra-rare disorder; findings derive from individual pedigrees and mechanistic experiments. Evidence type is indicated per claim: (human clinical), (in vitro), (human tissue), (yeast/comparative).

Summary

X-linked spondyloepiphyseal dysplasia tarda (SEDT) is a rare (~2 per 1,000,000), non-lethal, X-linked recessive osteochondrodysplasia caused by loss-of-function mutations in TRAPPC2 (SEDL) at Xp22.2, which encodes sedlin, a small 140-amino-acid protein. Sedlin is the Trs20 adaptor subunit of the conserved TRAPP tethering complex and a regulator of the secretory pathway. The central mechanistic insight is that SEDT is a disease of procollagen export from the endoplasmic reticulum in growth-plate chondrocytes: sedlin binds and promotes efficient cycling of the Sar1 GTPase, allowing nascent COPII carriers to enlarge into "megacarriers" capable of exporting bulky procollagen prefibrils. Loss of sedlin blocks this export, producing a secretory bottleneck (dilated rough ER) and defective chondrogenesis.

Clinically, affected hemizygous males are normal at birth and present in late childhood/adolescence (~5–14 y) with disproportionate short-trunk short stature, barrel chest, pathognomonic hump-shaped platyspondyly, and premature secondary osteoarthritis of the spine and hips. Because the defect is confined to the skeleton, metabolic laboratory values are normal (a key diagnostic discriminator from mucopolysaccharidoses) and life expectancy is normal. Female carriers are usually asymptomatic. Diagnosis rests on characteristic radiographs plus an X-linked pedigree, confirmed by TRAPPC2 sequencing.

There is no disease-modifying therapy. Management is symptomatic and orthopedic — NSAIDs, physiotherapy, joint protection, and total hip arthroplasty for end-stage hip osteoarthritis (which yields large functional gains). Prevention is reproductive/genetic: counseling, carrier testing, prenatal diagnosis, and PGT-M once the familial variant is known. This report presents eight confirmed findings, a stepwise causal model, the supporting evidence base, and the full 15-section disease-knowledge-base template.

Key Findings

Finding 1 — SEDT is caused by loss-of-function mutations in TRAPPC2/SEDL

SEDT is an X-linked recessive osteochondrodysplasia caused by mutations in TRAPPC2 (SEDL) that almost invariably eliminate functional sedlin (loss of function). Independent pedigrees across Japanese, Chinese, European, and Australian families show cosegregation under X-linked recessive inheritance, spanning nonsense (c.61G>T/p.E21 PMID: 24841781; S110X PMID: 12446987), frameshift (2-bp exon-5 deletion PMID: 11760838), splice-site (IVS2-2A>C → exon 3 skipping PMID: 16120574; recurrent c.93+5G>A PMID: 11326333; c.93+5G>C PMID: 23876379), and intragenic deletions removing the start codon (PMID: 11252002). The Japanese family study established the mechanism directly: "The nature of the mutation predicted that the SEDL protein (Sedlin) was not produced in the proband, indicating that loss of Sedlin caused SEDT" (PMID: 11252002). A splice study confirmed the same logic — because the start site is on exon 3 — "the splicing defect causes affected individuals failure to produce sedlin, which elucidates the causative role of SEDL gene" (PMID: 16120574). Inheritance and clinical hallmark were summarized in a five-generation Chinese pedigree: "Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive osteochondrodysplasia characterized by disproportionately short stature and degenerative joint disease" (PMID: 24841781). Ontology:* HGNC:23068 (TRAPPC2); MONDO:0010737.

Finding 2 — Sedlin promotes ER export of procollagen by regulating the Sar1 GTPase cycle

The landmark study of Venditti et al. (2012) defined sedlin's molecular function and linked it to tissue pathology: the cargo receptor TANGO1 recruits sedlin, which is required for ER export of procollagen (PC). "Sedlin bound and promoted efficient cycling of Sar1" — the GTPase that controls COPII budding (PMID: 23019651). By promoting Sar1 turnover, sedlin lets COPII carriers grow into megacarriers large enough for bulky procollagen prefibrils. Critically, "this joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT" (PMID: 23019651). Biochemical studies show disease missense mutants S73L, F83S, and V130D misfold and are proteasomally degraded (rescued by MG132), while D47Y folds normally but has altered Bet3 binding — two routes to loss of function (PMID: 19650763). The same study localized sedlin to "proliferating and hypertrophic chondrocytes" (PMID: 19650763), the growth-plate cells where the defect manifests. Ontology: GO:0006888 (ER-to-Golgi transport); GO:0090110 (COPII cargo loading); CL:0000138 (chondrocyte).

Finding 3 — Clinical hallmark: short-trunk short stature, hump-shaped platyspondyly, premature osteoarthritis

Affected hemizygous males present in late childhood/adolescence with disproportionately short trunk/stature and a barrel-chest deformity: "presents with disproportionate short stature and 'barrel-chest' deformity in affected (hemizygous) adolescent boys" (PMID: 11760838). The radiographic hallmark is platyspondyly with a hump-shaped (posterior/central) vertebral mound, end-plate sclerosis, disc-space narrowing, short thick femoral necks, narrow hips, and pelvic osteosclerosis: "His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis" (PMID: 32471379), and "Radiographically the disorder is characterized by a typical hump-shaped deformity of the vertebral bodies" (PMID: 15221797). Early degenerative joint disease of spine and hips is near-universal; carriers are usually asymptomatic (PMID: 11760838). Ontology (HPO): HP:0000926 (Platyspondyly); HP:0004322 (Short stature); HP:0002758 (Osteoarthritis); HP:0002656 (Epiphyseal dysplasia).

Finding 4 — Gene structure, epidemiology, and X-inactivation escape

SEDL/TRAPPC2 maps to Xp22.2, is a 2.8-kb transcript expressed broadly including fetal cartilage, and encodes sedlin, 140 aa: "SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport" (PMID: 10431248). Prevalence: "an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people" (PMID: 10431248). The gene escapes X-inactivation — "RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation" (PMID: 11326333) — has a transcribed retropseudogene on chr19, and conserved orthologues from yeast (p20/Trs20) to mammals. The recurrent c.93+5G>A allele appears in multiple unrelated families (PMID: 11326333, PMID: 26252088).

Finding 5 — Ultrastructural pathology confirms a secretory-pathway defect

Articular cartilage from an adult SEDT patient carrying c.93+5G>A contained chondrocytes with abundant Golgi and dilated rough ER: "Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER)" (PMID: 11326333). The distended ER is the morphological signature of a secretory bottleneck (procollagen retention). The authors concluded: "These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis" (PMID: 11326333). Ontology: GO:0005783 (ER); GO:0005794 (Golgi).

Finding 6 — Sedlin (Trs20) is an essential TRAPP adaptor with Rab-GEF activity

TRAPP is a conserved modular "transport protein particle" complex acting as a Ypt/Rab GTPase GEF: "TRAPP attracted attention when it was shown to act as a Ypt/Rab GTPase nucleotide exchanger, GEF" (PMID: 27066478). Sedlin is the adaptor for higher-order assembly: "Another small subunit, Trs20/Sedlin, is an adaptor required for the association of core TRAPP with larger subunits to form TRAPP II and TRAPP III" (PMID: 27066478). TRAPP regulates both secretion and autophagy, so sedlin loss could in principle affect both; the secretory (procollagen) branch is the demonstrated driver of SEDT. Ontology: GO:0030008 (TRAPP complex); GO:0006914 (autophagy — inferred).

Finding 7 — Management is orthopedic; total hip arthroplasty is effective for end-stage hip OA

No curative therapy exists; care is supportive/orthopedic. Because the dysplasia "usually leads to premature secondary osteoarthritis often requiring hip arthroplasty" (PMID: 10431248), THA is the mainstay for end-stage disease. In a series of SED patients with Tönnis grade 3 hip OA, THA improved mean Harris hip score from 35.55 preoperatively to 89.56, with reduced pain (VAS) and improved SF-12, and low short-term complications (PMID: 33550353). Registry data show THA durability in pediatric hip diseases is comparable to primary OA after adjustment (PMID: 23043269). Life expectancy is normal: SEDT features "disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications" (PMID: 10431248). Ontology (NCIT): Total Hip Arthroplasty; NSAID Therapy; Physical Therapy.

Finding 8 — Diagnosis rests on radiographs plus normal labs and X-linked pedigree, confirmed by sequencing

Clinical diagnosis is challenging: "Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites [sic]. Genetic diagnosis is critical in both early diagnosis and management of the disease" (PMID: 32471379). The diagnostic triad is platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis (PMID: 32471379). Definitive diagnosis is by TRAPPC2 sequencing (ACMG-classified). Once the familial variant is known, "Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT" (PMID: 11760838). Key differential: SED tarda with progressive arthropathy (PPAC, WISP3/CCN6; PMID: 10870664), SED congenita (COL2A1), multiple epiphyseal dysplasia, and mucopolysaccharidoses (abnormal urinary GAGs — absent in SEDT).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

A loss-of-function TRAPPC2 mutation in a hemizygous male leads to absent or misfolded sedlin (NMD of null alleles; proteasomal degradation of destabilizing missense mutants). (demonstrated — PMID: 11252002, PMID: 19650763)
Loss of sedlin results in failure of its role as the Trs20 adaptor for TRAPP II/III assembly and loss of function at ER exit sites. (demonstrated in vitro — PMID: 27066478)
In chondrocytes, TANGO1 normally recruits sedlin, which binds and promotes efficient cycling of Sar1; without sedlin, Sar1 cycling is impaired and COPII carriers cannot enlarge into megacarriers. (demonstrated in vitro — PMID: 23019651)
Impaired megacarrier growth leads to defective ER export of procollagen (too large for standard COPII vesicles). (demonstrated in vitro — PMID: 23019651)
Procollagen accumulates in a dilated rough ER (with expanded Golgi) in patient chondrocytes — a secretory bottleneck. (demonstrated, human tissue — PMID: 11326333)
Reduced secretion of cartilage collagen matrix results in defective chondrogenesis/endochondral ossification at vertebral and epiphyseal growth plates (sedlin is expressed in proliferating/hypertrophic chondrocytes). (inferred from mechanism + expression — PMID: 19650763, PMID: 23019651)
Growth-plate dysfunction leads to the skeletal phenotype — platyspondyly, epiphyseal dysplasia, short trunk — visible only after years of growth (hence "tarda"). (human clinical — PMID: 10431248, PMID: 15221797)
Abnormal joint/vertebral architecture results in altered biomechanics and premature secondary osteoarthritis of spine and hips → chronic pain and disability, treated by arthroplasty. (human clinical — PMID: 10431248, PMID: 33550353)

Branch point: TRAPP also functions in autophagy and general ER–Golgi trafficking (PMID: 27066478); in principle sedlin loss could perturb these broadly, yet the phenotype is skeleton-restricted — inferred to reflect the exceptionally high demand for large procollagen cargo export in chondrocytes rather than a global trafficking collapse.

TRAPPC2 (Xp22.2) loss-of-function mutation
│  absent / misfolded sedlin (Trs20)
▼
Defective TRAPP assembly + impaired Sar1 GTPase cycling
▼
COPII "megacarriers" fail to form ──► procollagen cannot exit ER
▼
Dilated rough ER + expanded Golgi in growth-plate chondrocytes (CL:0000138)
▼
Defective chondrogenesis / abnormal endochondral ossification
├──► Platyspondyly (hump-shaped vertebrae) ──► short-trunk stature, barrel chest
└──► Epiphyseal dysplasia (hips) ──► premature secondary osteoarthritis
                                             ▼
                                Total hip arthroplasty (symptomatic Tx)

Upstream vs downstream: mutation and sedlin loss are upstream; the Sar1/COPII/procollagen-export defect is the proximal molecular mechanism; ER distension and defective chondrogenesis are the cellular midpoints; the skeletal phenotype with secondary OA is the downstream endpoint. Cell type: growth-plate chondrocyte (CL:0000138). Anatomy: vertebral column (UBERON:0001130), epiphyseal plate (UBERON:0006255/0002515), hip joint (UBERON:0001464).

Full Disease-Knowledge-Base Template (Sections 1–15)

1. Disease Information

Overview. SEDT is a rare, non-lethal X-linked recessive osteochondrodysplasia affecting primarily the vertebrae (spondylo-) and epiphyses. It is "tarda" (late) because affected boys are normal at birth, with skeletal signs emerging typically between ~5 and 14 years. Cardinal features are disproportionate short-trunk short stature, a barrel/short chest, and characteristic platyspondyly with a hump-shaped mound on the central/posterior vertebral bodies, leading to premature secondary osteoarthritis of spine and large joints (especially hips) without systemic metabolic complications (PMID: 10431248, PMID: 15221797) (human clinical).

"Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people." (PMID: 10431248)

Key identifiers. - OMIM phenotype: 313400 (Spondyloepiphyseal dysplasia tarda, X-linked) - OMIM gene: 300202 (TRAPPC2 / SEDL) - Orphanet: ORPHA:93284 (X-linked spondyloepiphyseal dysplasia tarda) - ICD-10: Q77.7 (Spondyloepiphyseal dysplasia) - ICD-11: ~LD24.1 (spondyloepiphyseal dysplasias) — verify exact code - MeSH: Osteochondrodysplasias (D010009); no unique dedicated descriptor - MONDO: MONDO:0010737 - Gene: TRAPPC2 (HGNC:23068; formerly SEDL); NCBI Gene ID 6399; cytoband Xp22.2; protein sedlin

Synonyms. SEDT; SED tarda; SEDL; X-linked spondyloepiphyseal dysplasia; spondyloepiphyseal dysplasia tarda, X-linked; sedlin deficiency. (Autosomal "SED tarda with progressive arthropathy" is genetically distinct — see §10.)

Evidence source: aggregated disease-level resources (OMIM, Orphanet) + individual pedigrees; not EHR/population data.

2. Etiology

Primary cause — genetic (monogenic). SEDT is caused by loss-of-function mutations in TRAPPC2/SEDL on Xp22.2 encoding sedlin (PMID: 10431248, PMID: 11252002) (human clinical). It is not infectious, environmental, or multifactorial.

Genetic risk factors. Hemizygous pathogenic TRAPPC2 variants in males essentially fully determine disease. Male sex and an affected/carrier mother are the defining risk determinants (X-linked recessive). No susceptibility loci or modifier genes are established.

Protective factors. In heterozygous females, a normal X allele plus random X-inactivation renders most carriers asymptomatic (dosage protection). No protective modifier alleles described.

Environmental risk/protective factors & gene–environment interactions. None recognized — as expected for a fully penetrant Mendelian trafficking defect. Phenotypic variability exists (severe child vs mild adult, PMID: 11491516) but no molecular modifier has been mapped.

3. Phenotypes

All phenotypes are physical manifestations / clinical signs of a skeletal dysplasia; there are no characteristic laboratory abnormalities (normal blood/urine chemistry, normal mucopolysaccharides), a key diagnostic discriminator (PMID: 32471379). Onset is childhood (~5–14 y); course is chronic and slowly progressive; penetrance in hemizygous males is essentially complete with variable expressivity.

Phenotype	Type	Onset / severity / frequency	Suggested HPO
Platyspondyly with hump-shaped vertebral mound	Radiographic sign (pathognomonic)	Childhood; near-universal	HP:0000926 (Platyspondyly)
Disproportionate short-trunk short stature	Physical	Childhood; mild–moderate	HP:0004322 (Short stature); HP:0004600 (short trunk, verify)
Short neck / barrel (short) chest	Physical	Childhood; common	HP:0000765 (Abnormal thorax)
Early-onset osteoarthritis (spine, hips)	Clinical sign	Adolescence–adulthood; progressive; near-universal	HP:0002758 (Osteoarthritis)
Chronic back pain	Symptom	Adolescence/adult; frequent	HP:0003418 (Back pain)
Hip pain / coxarthrosis	Symptom/sign	Adult; frequent; may need arthroplasty	Hip osteoarthritis (verify)
Epiphyseal dysplasia; short/thick femoral necks	Radiographic	Childhood; common	HP:0002656; HP:0100864 (short femoral neck)
Kyphosis / scoliosis	Physical	Childhood/adolescence; variable	HP:0002808; HP:0002650
Narrow disc spaces, end-plate sclerosis	Radiographic	Childhood/adolescence	Abnormal vertebral morphology
Pelvic osteosclerosis, small iliac wings	Radiographic	Childhood	Abnormal pelvis morphology

Quality-of-life impact. Morbidity is musculoskeletal: chronic back and hip pain, reduced mobility/stamina, and functional limitation from early OA dominate. Instruments used in SED hip-OA literature include Harris Hip Score, WOMAC, VAS, SF-12 (PMID: 33550353). No cognitive, cardiac, respiratory-failure, or visceral involvement.

4. Genetic / Molecular Information

Causal gene. TRAPPC2 (SEDL), Xp22.2, HGNC:23068, NCBI Gene 6399, OMIM 300202; encodes sedlin (140 aa), a 2.8-kb transcript expressed broadly including fetal cartilage (PMID: 10431248). A near-identical paralog TRAPPC2B and a transcribed retropseudogene on chr19 exist — relevant to assay design (PMID: 11326333).

Pathogenic variant spectrum (all germline; LoF). - Frameshift/indels: dinucleotide deletions with premature stops (PMID: 10431248); 2-bp exon-5 deletion (PMID: 11760838); additional small indels (PMID: 15221797). - Nonsense: c.61G>T/p.E21 (PMID: 24841781); S110X (PMID: 12446987). - Splice-site: recurrent c.93+5G>A (IVS3+5G>A) hot spot causing exon-3 skipping (PMID: 11326333, PMID: 26252088); c.93+5G>C (PMID: 23876379); IVS2-2A>C (PMID: 16120574). - Missense: D47Y, S73L, F83S, V130D (PMID: 19650763); c.218C>T (PMID: 18247296) — rarer; mostly destabilize the protein. - Gross deletions:* intragenic deletion removing the start codon/exon 3 (PMID: 11252002); whole-exon deletions (PMID: 15221797).

Functional consequence: predominantly loss of function / absence of sedlin (NMD, no protein, or misfolded protein degraded by the proteasome) (PMID: 11252002, PMID: 19650763). No gain-of-function or dominant-negative mechanism. Missense S73L/F83S/V130D misfold and are proteasomally degraded (rescued by MG132); D47Y folds normally but shows altered Bet3 binding (PMID: 19650763) (in vitro).

Variant classification. Reported variants are Pathogenic/Likely pathogenic under ACMG criteria (null variants in a LoF gene; cosegregation; absent from controls/gnomAD) (PMID: 32471379). Allele frequency: disease alleles absent/ultra-rare in gnomAD/1000 Genomes; absent from ≥100 control chromosomes in multiple studies (PMID: 11326333, PMID: 23876379).

Somatic vs germline: entirely germline. Modifiers/epigenetic/chromosomal: none established; the gene escapes X-inactivation (PMID: 11326333), possibly explaining subtle carrier changes. Ontology: GO:0005085 (GEF activity); GO:0030008 (TRAPP complex).

5. Environmental Information

Not applicable. SEDT is a pure monogenic disorder. No environmental toxins, radiation, occupational exposures, lifestyle factors, or infectious agents cause or trigger it. Mechanical joint loading over time contributes to the progression of secondary osteoarthritis (a biomechanical, not etiologic, factor); activity modification is advised clinically but is not an etiologic environmental factor.

6. Mechanism / Pathophysiology

(See the Mechanistic Model above for the numbered causal chain.)

Category detail. - Molecular pathways: COPII vesicle biogenesis / ER-to-Golgi anterograde transport; Sar1 GTPase cycle; TRAPP-mediated Rab (Ypt1/Rab1) GEF activity (Reactome "COPII-mediated vesicle transport"). GO:0006888; GO:0090110. - Cellular processes: secretory protein trafficking; possible autophagy modulation; ER cargo retention / plausible ER stress (dilated RER; GO:0030968 UPR not proven). - Protein dysfunction: LoF via misfolding/degradation or absent protein; altered partner binding (Bet3, TANGO1, Sar1) (PMID: 19650763, PMID: 23019651). - Metabolic / immune changes: none characteristic. - Tissue damage mechanism: structural/matrix insufficiency and biomechanical wear (osteoarthritic cartilage degeneration), not oxidative/ischemic/fibrotic primary injury. - Molecular profiling (omics): No large transcriptomic/proteomic/metabolomic disease datasets exist (rare disease); mechanistic data are from targeted in vitro procollagen-export and biochemical assays. - Cell types (CL): chondrocyte (CL:0000138), proliferating/hypertrophic growth-plate chondrocytes. Subcellular (GO CC): ER (GO:0005783), ER exit site (GO:0070971), Golgi (GO:0005794), COPII coat (GO:0030127), TRAPP complex (GO:0030008).

7. Anatomical Structures Affected

Organ/system level: the skeletal (musculoskeletal) system is the sole primary system. Primary sites: vertebral column (UBERON:0001130) and epiphyses/growth plates (UBERON:0002515 epiphysis; UBERON:0006255 epiphyseal plate). Secondary: hip joint (UBERON:0001464), femoral head/neck, pelvis (UBERON:0001270), thorax/rib cage (UBERON:0001443). No cardiovascular, nervous, respiratory-failure, digestive, endocrine, ocular, or renal involvement.
Tissue/cell level: cartilage/connective tissue (UBERON:0002418); target cell = chondrocyte (CL:0000138).
Subcellular level: ER (GO:0005783), Golgi (GO:0005794), COPII/ER-exit machinery.
Localization/lateralization: generalized, bilateral/symmetric axial + appendicular involvement.

8. Temporal Development

Onset: pediatric/childhood, typically 5–14 y; insidious/chronic; normal at birth (distinguishes from SED congenita). Presymptomatic diagnosis possible by imaging/DNA (PMID: 11760838).
Progression: slowly progressive; growth-plate phenotype consolidates through skeletal growth, then secondary osteoarthritis progresses through adulthood (early → end-stage, e.g., Tönnis grade 3 hip OA, PMID: 33550353).
Course/duration: chronic, lifelong, non-remitting; not episodic.
Critical period: the skeletal-growth years are the biologically relevant window for any hypothetical disease-modifying therapy; none currently exists.

9. Inheritance and Population

Inheritance: X-linked recessive; affected hemizygous males; obligate female carriers usually asymptomatic (gene escapes X-inactivation) (PMID: 10431248, PMID: 11326333).
Penetrance: essentially complete in males (age-dependent expression). Expressivity: variable (PMID: 11491516).
Epidemiology: prevalence ≈ 2 per 1,000,000 (0.2/100,000) (PMID: 10431248); incidence not separately reported; pan-ethnic (Europe, China, Japan, Australia).
Sex ratio: strongly male-predominant.
Founder effects/consanguinity: no classical founder mutation, but c.93+5G>A is a recurrent hot spot (PMID: 11326333, PMID: 15221797); consanguinity not required.
Anticipation/mosaicism: no anticipation (not a repeat disorder); germline mosaicism not specifically documented. Carrier frequency: not formally established; disease alleles ultra-rare in gnomAD.

10. Diagnostics

Imaging (primary modality): spinal/pelvic radiographs show pathognomonic platyspondyly with hump-shaped vertebral bodies, end-plate sclerosis, narrow disc spaces, short/thick femoral necks, narrow hips, pelvic osteosclerosis (PMID: 10431248, PMID: 32471379).
Laboratory/biomarkers: characteristically normal — no metabolic biomarker, normal urinary GAGs, normal blood chemistry; this normality is itself discriminating (rules out MPS; PMID: 32471379).
Histopathology/ultrastructure: chondrocytes with dilated rough ER and abundant Golgi on EM (PMID: 11326333) — supportive, not routine.
Genetic testing (confirmatory): single-gene sequencing of TRAPPC2 (6 exons + splice sites); deletion/duplication analysis (CMA/MLPA) for gross deletions (PMID: 11252002, PMID: 15221797). WES/WGS or skeletal-dysplasia panels for atypical cases (PMID: 32471379). RT-PCR confirms splice effects (PMID: 16120574). Assays must avoid the chr19 pseudogene/TRAPPC2B paralog (PMID: 11326333). Karyotype/FISH/mtDNA/repeat testing not applicable.
Differential diagnosis:

Condition	Distinguishing feature
SED tarda with progressive arthropathy (PPAC)	WISP3/CCN6; inflammatory hand/wrist arthropathy; AR (PMID: 10870664)
SED congenita	COL2A1; neonatal onset; ocular/cleft palate
Multiple epiphyseal dysplasia	epiphyses without vertebral hump
Mucopolysaccharidoses (Morquio)	abnormal urinary GAGs; visceral/corneal involvement
Scheuermann / post-SCFE / Kashin-Beck	no X-linked pedigree; no generalized platyspondyly

Screening: no newborn/population screening; cascade testing of at-risk male relatives and carrier testing of females is appropriate; presymptomatic diagnosis feasible (PMID: 11760838).

11. Outcome / Prognosis

Survival/mortality: normal life expectancy; no disease-specific mortality ("absence of systemic complications," PMID: 10431248).
Morbidity/disability: significant musculoskeletal morbidity — chronic back/hip pain, restricted mobility, short stature, and early osteoarthritis often requiring joint arthroplasty (PMID: 10431248, PMID: 33550353). Disability is functional/orthopedic (ICF: mobility, pain), not cognitive/visceral.
QoL measures: Harris Hip Score, WOMAC, VAS, SF-12 (PMID: 33550353).
Recovery: the dysplasia is not reversible, but arthroplasty markedly improves pain and function (Harris Hip Score ~35.6 → 89.6; PMID: 33550353).
Prognostic factors: severity/rate of joint degeneration and degree of short stature/kyphoscoliosis. No molecular prognostic biomarker; genotype–phenotype correlation weak (PMID: 11491516).

12. Treatment

No curative or disease-modifying therapy exists. Management is symptomatic, orthopedic, and rehabilitative (NCIT terms in brackets).

Pharmacotherapy: analgesics and NSAIDs for joint/back pain [NCIT: Nonsteroidal Anti-inflammatory Agent; Analgesic Therapy]. No SEDT-specific pharmacogenomics.
Surgical/interventional: Total hip arthroplasty (THA) for end-stage hip OA — effective, low short-term complications, large functional gains (PMID: 33550353) [NCIT: Total Hip Arthroplasty]. Spinal surgery for severe kyphoscoliosis; osteotomy in selected joints.
Supportive/rehabilitative: physical therapy, weight management, activity modification, pain management, mobility aids [NCIT: Physical Therapy; Rehabilitation Therapy; Pain Management].
Advanced therapeutics (gene/cell/RNA/targeted/immuno): none approved or in trials for SEDT. The LoF mechanism and defined Sar1/procollagen pathway make it a theoretical gene-replacement target, but no program exists.
Experimental/clinical trials: no disease-specific interventional trials identified.
Strategy/personalized medicine: genotype-guided therapy not applicable; management guided by orthopedic severity; genetic counseling is core [NCIT: Genetic Counseling].
Adverse events: chronic NSAID risks and standard arthroplasty risks; SED THA survivorship favorable and comparable to other pediatric hip-disease groups after adjustment (PMID: 23043269).

13. Prevention

Primary prevention: not possible for a germline monogenic disorder. Reproductive/genetic prevention is the principal lever: genetic counseling, carrier testing of at-risk females, prenatal diagnosis, and PGT-M once the familial TRAPPC2 variant is known (PMID: 24841781, PMID: 23876379). Carrier females have 50% transmission risk (affected sons, carrier daughters).
Secondary prevention: cascade testing and early radiographic surveillance of at-risk boys enables early orthopedic monitoring; presymptomatic diagnosis feasible (PMID: 11760838).
Tertiary prevention: joint protection, weight control, physiotherapy, timely orthopedic intervention to preserve function and optimize arthroplasty timing.
Immunization/public health/environmental: not applicable.

14. Other Species / Natural Disease

Taxonomy: disease described in Homo sapiens (NCBI:txid9606) only.
Orthologous genes: sedlin/TRAPPC2 is deeply conserved: mouse Trappc2, rat, zebrafish trappc2, Drosophila, C. elegans, and S. cerevisiae TRS20 (p20) (PMID: 11326333, PMID: 10431248). Yeast p20/Trs20 has a role in ER-to-Golgi transport (PMID: 11326333).
Natural disease in animals: no naturally occurring animal model of SEDT is documented in OMIA (knowledge gap).
Comparative biology: the ER-to-Golgi TRAPP/Sar1 mechanism is conserved from yeast to humans, so the molecular pathway is highly conserved even though the skeletal disease is human-specific (chondrocyte/procollagen context).
Transmission/zoonosis: not applicable (non-infectious).

15. Model Organisms

In vitro/cellular models (primary evidence base): patient-derived and transfected cell systems showing mislocalization, misfolding, and proteasomal degradation of mutant sedlin, and altered Bet3 binding (PMID: 19650763) (in vitro); biochemical reconstitution of procollagen ER export demonstrating the TANGO1–Sedlin–Sar1 axis and megacarrier formation (PMID: 23019651) (in vitro); mouse growth-plate tissue for in situ localization of sedlin to proliferating/hypertrophic chondrocytes (PMID: 19650763).
Yeast (S. cerevisiae) TRS20: the tractable genetic model that defined TRAPP subunit architecture and Rab-GEF function (PMID: 27066478, PMID: 11326333).
Genetic vertebrate models: no widely reported mouse/zebrafish model faithfully recapitulates the human SEDT skeletal phenotype — a notable knowledge gap. Orthologs are amenable to knockout via MGI/ZFIN resources.
Applications: existing models best dissect the secretory-trafficking mechanism (procollagen export, Sar1 cycling) rather than whole-organism skeletal disease.
Limitations: cell/yeast models do not reproduce growth-plate architecture, endochondral ossification, or biomechanical progression to OA.
Resource databases: MGI (Trappc2), ZFIN (trappc2), SGD (TRS20), Alliance of Genome Resources.

Evidence Base

PMID	Title (abbrev.)	Role in this report
10431248	Identification of the gene (SEDL) causing SEDT	Gene ID, prevalence, 140-aa protein, ER-Golgi role, normal lifespan/arthroplasty
11252002	Loss of Sedlin causes X-linked SEDT (Japanese family)	Loss of sedlin as disease mechanism
11326333	Recurrent RNA-splicing mutation in SEDL	c.93+5G>A hot spot; X-inactivation escape; dilated rough ER
16120574	Novel splicing mutation IVS2-2A>C	Exon-3 skipping abolishes sedlin
24841781	Nonsense mutation, 5-gen Chinese pedigree	X-linked recessive; clinical hallmark; p.E21*
12446987	Novel nonsense mutation S110X	Nonsense spectrum
11760838	Preonset studies; 2-bp deletion	Onset age/sex; barrel chest; carrier/prenatal testing
23019651	Sedlin controls ER export of procollagen via Sar1	Core molecular mechanism; chondrogenesis link
19650763	Biochemical consequences of sedlin mutations	Missense misfolding/degradation; chondrocyte expression
15221797	Mutations in 13 European families	Hump-shaped vertebral deformity as hallmark
32471379	Novel TRAPPC2 deletion, Chinese family	Diagnostic triad; normal labs; genetic diagnosis critical
27066478	TRAPP Complexes in Secretion and Autophagy	Sedlin/Trs20 adaptor; Rab-GEF; two pathways
33550353	THA for Tönnis grade 3 hip OA in SED	THA efficacy (Harris 35.6→89.6)
23043269	Low revision rate THA, pediatric hip diseases	THA durability
10870664	SEDT with progressive arthropathy	Differential (PPAC, WISP3/CCN6)
23876379	Novel splicing mutation, Chinese pedigree	c.93+5G>C; splice LoF
18247296	Missense mutation, Chinese family	c.218C>T; carrier genotype-phenotype
26252088	TRAPPC2 mutation analysis	Independent confirmation of c.93+5G>A
11491516	Severe child vs mild adult features	Variable expressivity

Evidence-source distinction. The mechanistic backbone (sedlin→Sar1→procollagen export) derives from in vitro / cell-biology studies (PMID: 23019651, PMID: 19650763, PMID: 27066478). Genotype–phenotype and clinical/radiographic data are human clinical studies from multiple independent pedigrees. Ultrastructural pathology is human tissue (PMID: 11326333). Treatment-efficacy data are human clinical case series/registries but drawn from SED broadly rather than SEDT specifically.

Limitations and Knowledge Gaps

Treatment evidence is indirect. THA outcome data (PMID: 33550353, PMID: 23043269) come from mixed SED / pediatric hip-disease cohorts, not SEDT-specific series; effect sizes should be extrapolated cautiously.
No validated animal model faithfully reproduces the SEDT skeletal phenotype; steps 6–7 of the causal chain remain inferred in vivo.
Weak genotype–phenotype correlation. Variable expressivity is documented (PMID: 11491516) but no modifier genes identified.
Carrier phenotype vs X-inactivation escape incompletely reconciled — carriers are largely asymptomatic despite escape (PMID: 11326333).
Autophagy branch of TRAPP (PMID: 27066478) not evaluated in SEDT chondrocytes.
Coarse epidemiology. The ~2/1,000,000 estimate is legacy; incidence, geographic distribution, and true carrier frequency (gnomAD) not quantified.
No SEDT-specific QoL data; inferences rest on generic SED/THA instruments.
Exact ICD-11 code and some HPO term IDs should be verified against current ontology releases.

Proposed Follow-up Experiments / Actions

Interrogate gnomAD/ClinVar systematically for TRAPPC2 LoF allele frequencies to refine carrier frequency, prevalence, and the ACMG-classified variant catalog.
Generate a chondrocyte-specific Trappc2 conditional knockout mouse (e.g., Col2a1-Cre) to test in vivo whether procollagen-export failure produces platyspondyly and epiphyseal dysplasia — closing the inferred gap in causal steps 6–7.
Profile ER stress / UPR (BiP, CHOP, XBP1 splicing) in patient- or iPSC-derived chondrocytes to test whether chronic ER distension activates a pathogenic UPR.
Assess autophagic flux (LC3-II, p62) in sedlin-deficient chondrocytes to determine whether the TRAPP III/autophagy role contributes to cartilage pathology.
Explore proteostasis-directed therapeutics for destabilizing missense alleles (S73L/F83S/V130D rescued by proteasome inhibition, PMID: 19650763) — chemical chaperones as a possible allele-specific disease-modifying route.
Establish a SEDT natural-history registry with standardized radiographic staging, disease-specific + SF-36 QoL, and long-term arthroplasty outcomes.
Cryo-EM of the TANGO1–sedlin–Sar1–COPII assembly to define, at atomic resolution, how disease mutations disrupt megacarrier formation, informing rational therapeutic design.

Report compiled from an autonomous multi-iteration literature investigation (8 confirmed findings, 24 papers reviewed). All mechanistic and clinical claims are anchored to the cited primary literature with verified abstract quotations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	19
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	31
Resolved	28
Unresolved (possible confabulation)	1
Obsolete	0
Unverifiable	2
Terms whose name was checked	17
Terms named correctly	8
Terms named as a different term	1
Terms whose name is worth a second look	8

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

GO:0005783 (3 mentions) - the report calls it "ER", "Subcellular level: ER"; GO calls it endoplasmic reticulum**

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0004600 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0006888 (2 mentions) - the report calls it "ER-to-Golgi transport"; GO calls it endoplasmic reticulum to Golgi vesicle-mediated transport, and lists "ER to Golgi transport" among its other names
GO:0090110 (2 mentions) - the report calls it "COPII cargo loading"; GO calls it COPII-coated vesicle cargo loading
GO:0005794 (3 mentions) - the report calls it "Golgi"; GO calls it Golgi apparatus, and lists "Golgi" among its other names
GO:0006914 (1 mention) - the report calls it "autophagy — inferred"; GO calls it autophagy
UBERON:0001464 (2 mentions) - the report calls it "hip joint"; UBERON calls it hip, and lists "hip region" among its other names
HP:0000765 (1 mention) - the report calls it "Abnormal thorax"; HP calls it Abnormal thorax morphology, and lists "Abnormality of the thorax" among its other names
GO:0005085 (1 mention) - the report calls it "GEF activity"; GO calls it guanyl-nucleotide exchange factor activity, and lists "GEF" among its other names
UBERON:0002418 (1 mention) - the report calls it "Tissue/cell level: cartilage/connective tissue"; UBERON calls it cartilage tissue**, and lists "portion of cartilage tissue" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0005783 - called "ER", "Subcellular level:** ER"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

X-Linked Spondyloepiphyseal Dysplasia Tarda (SEDT) — Comprehensive Disease Report

Summary

Key Findings

Finding 1 — SEDT is caused by loss-of-function mutations in TRAPPC2/SEDL

Finding 2 — Sedlin promotes ER export of procollagen by regulating the Sar1 GTPase cycle

Finding 3 — Clinical hallmark: short-trunk short stature, hump-shaped platyspondyly, premature osteoarthritis

Finding 4 — Gene structure, epidemiology, and X-inactivation escape

Finding 5 — Ultrastructural pathology confirms a secretory-pathway defect

Finding 6 — Sedlin (Trs20) is an essential TRAPP adaptor with Rab-GEF activity

Finding 7 — Management is orthopedic; total hip arthroplasty is effective for end-stage hip OA

Finding 8 — Diagnosis rests on radiographs plus normal labs and X-linked pedigree, confirmed by sequencing

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Full Disease-Knowledge-Base Template (Sections 1–15)

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Unresolved terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver