Jeune Asphyxiating Thoracic Dystrophy

Mendelian MONDO:0018770 Ciliopathies Short-Rib Dysplasias

Jeune asphyxiating thoracic dystrophy (JATD), also known as Jeune syndrome, is an autosomal recessive skeletal ciliopathy characterized by a narrow, bell-shaped thorax with short ribs leading to respiratory insufficiency. It is genetically heterogeneous, caused by mutations in genes encoding components of the intraflagellar transport (IFT) machinery and dynein motor complexes essential for primary cilium function. Additional features include short limbs, polydactyly, renal cystic disease, hepatic fibrosis, and retinal dystrophy. JATD represents the mildest end of the short-rib polydactyly syndrome spectrum.

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1
Inheritance
3
Pathophys.
8
Phenotypes
4
Genes
3
Treatments
6
References
2
Deep Research
👪

Inheritance

1
Autosomal Recessive
Autosomal recessive inheritance with significant genetic heterogeneity. Multiple causative genes identified in the intraflagellar transport and dynein motor pathways.
Show evidence (1 reference)
PMID:17468754 SUPPORT
"Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia"
Confirms autosomal recessive inheritance of JATD.
⚙

Pathophysiology

3
Intraflagellar Transport Dysfunction
Mutations in IFT genes (IFT80, IFT140, IFT172, WDR19, and others) disrupt the bidirectional transport system within primary cilia. This impairs ciliary assembly, maintenance, and signaling, particularly Hedgehog pathway transduction required for skeletal development.
Intraflagellar Transport link Hedgehog Signaling link Cilium Assembly link
Primary Cilium link
Show evidence (2 references)
PMID:17468754 SUPPORT
"IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease."
Landmark paper establishing the first link between IFT dysfunction and human skeletal ciliopathy.
PMID:23339108 SUPPORT
"To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis."
Confirms multiple IFT/dynein genes are implicated in JATD, establishing genetic heterogeneity.
Dynein Motor Complex Deficiency
Mutations in DYNC2H1 (most common cause) and other dynein-2 complex genes (DYNC2LI1, WDR34, WDR60) disrupt retrograde intraflagellar transport, which is essential for cilium function and Hedgehog signal transduction in developing cartilage and other tissues.
Chondrocyte link
Retrograde Intraflagellar Transport link
Show evidence (2 references)
PMID:19442771 SUPPORT
"DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia."
Confirms DYNC2H1 encodes a dynein-2 motor component required for cilium generation and maintenance.
PMID:23456818 SUPPORT
"Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations"
Demonstrates that DYNC2H1 mutations cause retrograde IFT defects with accumulation of anterograde transport proteins at ciliary tips.
Renal Cystogenesis
Primary cilium dysfunction leads to renal cystic disease through disrupted planar cell polarity and flow-sensing mechanisms in renal tubular epithelium, similar to other ciliopathies such as autosomal recessive polycystic kidney disease.
Kidney Development link
Kidney link
Show evidence (1 reference)
PMID:17468754 SUPPORT Model Organism
"Knockdown of ift80 in zebrafish resulted in cystic kidneys"
Zebrafish ift80 knockdown recapitulates the renal cystic phenotype, confirming ciliary dysfunction causes renal cystogenesis.
●

Phenotypes

8
Digestive 1
Hepatic Fibrosis Hepatic fibrosis (HP:0001395)
Show evidence (1 reference)
PMID:23339108 SUPPORT
"Renal and liver diseases occurred respectively in 17% and 22% of cases"
Quantifies liver disease at 22% of postnatal JATD cases.
Eye 1
Retinal Dystrophy Retinal dystrophy (HP:0000556)
Show evidence (2 references)
PMID:23339108 SUPPORT
"retinal alteration was present in 50% of cases aged more than 5 years."
Quantifies retinal involvement at 50% of JATD patients over age 5.
PMID:17468754 SUPPORT
"retinal degeneration, cystic renal disease and polydactyly may be complicating features."
Lists retinal degeneration as a complicating feature of JATD.
Genitourinary 1
Renal Cystic Disease Renal cyst (HP:0000107)
Show evidence (1 reference)
PMID:23339108 SUPPORT
"Renal and liver diseases occurred respectively in 17% and 22% of cases"
Quantifies renal disease at 17% of postnatal JATD cases.
Limbs 2
Limb Shortening Limb undergrowth (HP:0009826)
Show evidence (1 reference)
PMID:19442771 SUPPORT
"characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof."
Lists short long bones as a characteristic feature of JATD.
Postaxial Polydactyly Postaxial polydactyly (HP:0100259)
Show evidence (2 references)
PMID:17468754 SUPPORT
"retinal degeneration, cystic renal disease and polydactyly may be complicating features."
Lists polydactyly as a complicating feature of JATD.
PMID:23456818 SUPPORT
"DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement."
DYNC2H1 patients largely lack polydactyly, demonstrating an important genotype-phenotype correlation.
Musculoskeletal 2
Narrow Thorax Narrow chest (HP:0000774)
Show evidence (2 references)
PMID:17468754 SUPPORT
"often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency"
Confirms constricted thorax as the cardinal feature causing respiratory failure and infant mortality in JATD.
PMID:19442771 SUPPORT
"Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof."
Lists narrow thorax as a defining feature of JATD.
Short Ribs Short ribs (HP:0000773)
Show evidence (1 reference)
PMID:23339108 SUPPORT
"Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof."
Confirms short ribs as a defining feature of JATD within the short rib polydactyly group.
Respiratory 1
Pulmonary Insufficiency Respiratory insufficiency (HP:0002093)
Show evidence (1 reference)
PMID:23339108 SUPPORT
"pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases."
Quantifies pulmonary insufficiency at 60% of postnatal JATD cases.
🧬

Genetic Associations

4
DYNC2H1 Mutations (Causative)
Show evidence (4 references)
PMID:19442771 SUPPORT
"identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children."
Identifies DYNC2H1 as a causative gene for JATD.
PMID:23456818 SUPPORT
"We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients."
Large cohort showing DYNC2H1 mutations in 41% of JATD patients, establishing it as the most common genetic cause.
PMID:23456818 SUPPORT
"DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD."
Important genotype-phenotype correlation showing DYNC2H1 patients have primarily skeletal disease.
+ 1 more reference
IFT80 Mutations (Causative)
Show evidence (2 references)
PMID:17468754 SUPPORT
"We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease."
First identification of IFT80 as a causative gene for JATD.
PMID:23339108 SUPPORT
"We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%)."
Confirms IFT80 is a rare cause of JATD at 5% of families.
IFT140 Mutations (Causative)
WDR19 Mutations (Causative)
💊

Treatments

3
Respiratory Support
Mechanical ventilation and respiratory support in neonates with severe thoracic restriction. May require prolonged ventilatory support or tracheostomy.
Thoracic Expansion Surgery
Action: surgical procedure MAXO:0000004
Located in: thorax Ontology label: thoracic segment of trunk UBERON:0000915
Vertical expandable prosthetic titanium rib (VEPTR) to increase thoracic volume and improve respiratory function. Surgery achieves nearly 70% survival compared to 70-80% mortality without treatment.
Show evidence (3 references)
PMID:25575358 SUPPORT
"Survival rate of the 22 patients was 68%."
Reports 68% survival rate with VEPTR surgical treatment.
PMID:25575358 SUPPORT
"The survival rate in JS with surgery was nearly 70% (compared with 70% to 80% mortality without treatment) with less ventilator dependence."
Demonstrates dramatic improvement in survival with VEPTR surgery compared to untreated JATD.
PMID:25575358 SUPPORT
"Average chest width increased from 121 to 168 mm at follow-up (P<0.001)."
Quantifies the significant increase in thoracic dimensions achieved by VEPTR expansion surgery.
Renal Management
Monitoring and management of progressive renal cystic disease, including dialysis or transplantation for end-stage renal failure.
{ }

Source YAML

click to show 
name: Jeune Asphyxiating Thoracic Dystrophy
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-02-17T21:53:14Z'
category: Mendelian
description: >
  Jeune asphyxiating thoracic dystrophy (JATD), also known as Jeune syndrome,
  is an autosomal recessive skeletal ciliopathy characterized by a narrow, bell-shaped
  thorax with short ribs leading to respiratory insufficiency. It is genetically
  heterogeneous, caused by mutations in genes encoding components of the intraflagellar
  transport (IFT) machinery and dynein motor complexes essential for primary cilium
  function. Additional features include short limbs, polydactyly, renal cystic
  disease, hepatic fibrosis, and retinal dystrophy. JATD represents the mildest
  end of the short-rib polydactyly syndrome spectrum.
disease_term:
  preferred_term: Jeune syndrome
  term:
    id: MONDO:0018770
    label: Jeune syndrome
parents:
- Ciliopathies
- Short-Rib Dysplasias
inheritance:
- name: Autosomal Recessive
  description: >
    Autosomal recessive inheritance with significant genetic heterogeneity.
    Multiple causative genes identified in the intraflagellar transport and
    dynein motor pathways.
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      Jeune asphyxiating thoracic dystrophy, an autosomal recessive
      chondrodysplasia
    explanation: >-
      Confirms autosomal recessive inheritance of JATD.
prevalence:
- population: Live births
  percentage: 1 in 100,000 to 1 in 130,000
  notes: >-
    Reported incidence estimates place Jeune syndrome in the very rare range,
    with most mortality concentrated in infancy from thoracic restriction and
    respiratory complications.
  evidence:
  - reference: PMID:20037857
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is estimated to occur in 1 per 100.000-130.000 live births."
    explanation: This case report abstract explicitly states a commonly cited incidence range for Jeune asphyxiating thoracic dystrophy.
pathophysiology:
- name: Intraflagellar Transport Dysfunction
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >
    Mutations in IFT genes (IFT80, IFT140, IFT172, WDR19, and others) disrupt
    the bidirectional transport system within primary cilia. This impairs ciliary
    assembly, maintenance, and signaling, particularly Hedgehog pathway transduction
    required for skeletal development.
  biological_processes:
  - preferred_term: Intraflagellar Transport
    term:
      id: GO:0042073
      label: intraciliary transport
  - preferred_term: Hedgehog Signaling
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      IFT80 mutations underlie a subset of Jeune asphyxiating thoracic
      dystrophy cases, establishing the first association of a defective
      intraflagellar transport (IFT) protein with human disease.
    explanation: >-
      Landmark paper establishing the first link between IFT dysfunction
      and human skeletal ciliopathy.
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been
      reported in ATD. The clinical and molecular heterogeneity leads to
      difficulties in the evaluation of the long-term prognosis.
    explanation: >-
      Confirms multiple IFT/dynein genes are implicated in JATD,
      establishing genetic heterogeneity.
- name: Dynein Motor Complex Deficiency
  description: >
    Mutations in DYNC2H1 (most common cause) and other dynein-2 complex genes
    (DYNC2LI1, WDR34, WDR60) disrupt retrograde intraflagellar transport,
    which is essential for cilium function and Hedgehog signal transduction
    in developing cartilage and other tissues.
  biological_processes:
  - preferred_term: Retrograde Intraflagellar Transport
    term:
      id: GO:0035735
      label: intraciliary transport involved in cilium assembly
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      DYNC2H1 is a component of a cytoplasmic dynein complex and is directly
      involved in the generation and maintenance of cilia.
    explanation: >-
      Confirms DYNC2H1 encodes a dynein-2 motor component required for
      cilium generation and maintenance.
  - reference: PMID:23456818
    reference_title: "Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement."
    supports: SUPPORT
    snippet: >-
      Assessment of fibroblasts from patients showed accumulation of
      anterograde IFT proteins in the ciliary tips, confirming defects
      similar to patients with other retrograde IFT machinery mutations
    explanation: >-
      Demonstrates that DYNC2H1 mutations cause retrograde IFT defects
      with accumulation of anterograde transport proteins at ciliary tips.
- name: Renal Cystogenesis
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  description: >
    Primary cilium dysfunction leads to renal cystic disease through
    disrupted planar cell polarity and flow-sensing mechanisms in renal
    tubular epithelium, similar to other ciliopathies such as autosomal
    recessive polycystic kidney disease.
  biological_processes:
  - preferred_term: Kidney Development
    term:
      id: GO:0001822
      label: kidney development
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      Knockdown of ift80 in zebrafish resulted in cystic kidneys
    explanation: >-
      Zebrafish ift80 knockdown recapitulates the renal cystic phenotype,
      confirming ciliary dysfunction causes renal cystogenesis.
    evidence_source: MODEL_ORGANISM
phenotypes:
- name: Narrow Thorax
  description: >
    Characteristic narrow, bell-shaped thorax with short horizontal ribs.
    The cardinal feature causing respiratory insufficiency, which is the
    primary cause of mortality in infancy.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      often leads to death in infancy because of a severely constricted
      thoracic cage and respiratory insufficiency
    explanation: >-
      Confirms constricted thorax as the cardinal feature causing
      respiratory failure and infant mortality in JATD.
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive
      chondrodysplasia characterized by short ribs and a narrow thorax,
      short long bones, inconstant polydactyly, and trident acetabular roof.
    explanation: >-
      Lists narrow thorax as a defining feature of JATD.
- name: Short Ribs
  description: >
    Horizontally oriented short ribs contributing to the constricted
    thoracic cage and respiratory compromise.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib
      polydactyly group and is characterized by a narrow thorax, short
      long bones and trident acetabular roof.
    explanation: >-
      Confirms short ribs as a defining feature of JATD within the
      short rib polydactyly group.
- name: Limb Shortening
  description: >
    Rhizomelic or mesomelic limb shortening, variable in severity.
  phenotype_term:
    preferred_term: Limb undergrowth
    term:
      id: HP:0009826
      label: Limb undergrowth
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      characterized by short ribs and a narrow thorax, short long bones,
      inconstant polydactyly, and trident acetabular roof.
    explanation: >-
      Lists short long bones as a characteristic feature of JATD.
- name: Postaxial Polydactyly
  description: >
    Postaxial polydactyly of hands and/or feet, present in a subset
    of patients. DYNC2H1 patients tend to lack polydactyly.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      retinal degeneration, cystic renal disease and polydactyly may be
      complicating features.
    explanation: >-
      Lists polydactyly as a complicating feature of JATD.
  - reference: PMID:23456818
    reference_title: "Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement."
    supports: SUPPORT
    snippet: >-
      DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy
      (Jeune syndrome) without major polydactyly, renal or retinal involvement.
    explanation: >-
      DYNC2H1 patients largely lack polydactyly, demonstrating an important
      genotype-phenotype correlation.
- name: Renal Cystic Disease
  description: >
    Progressive renal cystic disease that may lead to renal failure.
    Occurs in a significant proportion of patients who survive infancy,
    reported in 17% of postnatal cases.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      Renal and liver diseases occurred respectively in 17% and 22% of cases
    explanation: >-
      Quantifies renal disease at 17% of postnatal JATD cases.
- name: Hepatic Fibrosis
  description: >
    Hepatic fibrosis and biliary dysgenesis, part of the ciliopathy
    spectrum affecting hepatobiliary development. Reported in 22%
    of postnatal cases.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      Renal and liver diseases occurred respectively in 17% and 22% of cases
    explanation: >-
      Quantifies liver disease at 22% of postnatal JATD cases.
- name: Retinal Dystrophy
  description: >
    Retinal degeneration may occur as part of the ciliopathy phenotype.
    Present in 50% of cases older than 5 years, more frequent than
    previously appreciated.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      retinal alteration was present in 50% of cases aged more than 5 years.
    explanation: >-
      Quantifies retinal involvement at 50% of JATD patients over age 5.
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      retinal degeneration, cystic renal disease and polydactyly may be
      complicating features.
    explanation: >-
      Lists retinal degeneration as a complicating feature of JATD.
- name: Pulmonary Insufficiency
  description: >
    Respiratory insufficiency from thoracic restriction is the primary
    cause of mortality. Noted in 60% of postnatal cases, with some
    requiring tracheostomy.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      pulmonary insufficiency was noted in 60% of cases, with tracheotomy
      requirement in five cases.
    explanation: >-
      Quantifies pulmonary insufficiency at 60% of postnatal JATD cases.
genetic:
- name: DYNC2H1 Mutations
  association: Causative
  notes: >
    Biallelic mutations in DYNC2H1, encoding the heavy chain of
    cytoplasmic dynein-2. The most common genetic cause of JATD,
    accounting for 33-59% of families depending on the cohort.
    DYNC2H1 patients tend to have a primarily skeletal phenotype
    without major extra-skeletal involvement.
  evidence:
  - reference: PMID:19442771
    reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
    supports: SUPPORT
    snippet: >-
      identified homozygous mutations in the cytoplasmic dynein 2 heavy
      chain 1 (DYNC2H1) gene in the affected children.
    explanation: >-
      Identifies DYNC2H1 as a causative gene for JATD.
  - reference: PMID:23456818
    reference_title: "Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement."
    supports: SUPPORT
    snippet: >-
      We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57
      families (33%), showing it as a major cause of JATD especially in
      Northern European patients.
    explanation: >-
      Large cohort showing DYNC2H1 mutations in 41% of JATD patients,
      establishing it as the most common genetic cause.
  - reference: PMID:23456818
    reference_title: "Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement."
    supports: SUPPORT
    snippet: >-
      DYNC2H1 patients largely lacked significant extra-skeletal involvement,
      demonstrating an important genotype-phenotype correlation in JATD.
    explanation: >-
      Important genotype-phenotype correlation showing DYNC2H1 patients
      have primarily skeletal disease.
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      We identified DYNC2H1 mutations in 23 families (59%) and IFT80
      mutations in two families (5%).
    explanation: >-
      French cohort showing DYNC2H1 mutations in 59% of JATD families.
- name: IFT80 Mutations
  association: Causative
  notes: >
    Biallelic mutations in IFT80, encoding intraflagellar transport
    protein 80. IFT80 is a component of the IFT-B complex required
    for anterograde transport in cilia. A rare cause of JATD (5%).
  evidence:
  - reference: PMID:17468754
    reference_title: "IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy."
    supports: SUPPORT
    snippet: >-
      We show that IFT80 mutations underlie a subset of Jeune asphyxiating
      thoracic dystrophy cases, establishing the first association of a
      defective intraflagellar transport (IFT) protein with human disease.
    explanation: >-
      First identification of IFT80 as a causative gene for JATD.
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    snippet: >-
      We identified DYNC2H1 mutations in 23 families (59%) and IFT80
      mutations in two families (5%).
    explanation: >-
      Confirms IFT80 is a rare cause of JATD at 5% of families.
- name: IFT140 Mutations
  association: Causative
  notes: >
    Biallelic mutations in IFT140, encoding a component of the IFT-A
    complex involved in retrograde intraflagellar transport.
- name: WDR19 Mutations
  association: Causative
  notes: >
    Biallelic mutations in WDR19, encoding another IFT-A complex
    component. WDR19 mutations also cause cranioectodermal dysplasia
    and nephronophthisis.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    Jeune asphyxiating thoracic dystrophy is diagnosed from the characteristic
    narrow thorax, short long bones, and trident acetabular roof on
    radiographs, with attention to renal, hepatic, and retinal involvement, and
    is confirmed by molecular genetic testing of the short-rib/ciliopathy genes
    (most often DYNC2H1). It belongs to the short-rib polydactyly / skeletal
    ciliopathy spectrum.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof."
    explanation: >-
      Defines the clinical/radiographic diagnostic hallmarks and the
      short-rib-polydactyly spectrum placement of ATD.
  - reference: PMID:23339108
    reference_title: "Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that DYNC2H1 is a major gene responsible for ATD"
    explanation: >-
      Supports DYNC2H1 as the principal molecular diagnostic target in ATD.
treatments:
- name: Respiratory Support
  description: >
    Mechanical ventilation and respiratory support in neonates with
    severe thoracic restriction. May require prolonged ventilatory
    support or tracheostomy.
- name: Thoracic Expansion Surgery
  description: >
    Vertical expandable prosthetic titanium rib (VEPTR) to increase
    thoracic volume and improve respiratory function. Surgery achieves
    nearly 70% survival compared to 70-80% mortality without treatment.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
    located_in:
      preferred_term: thorax
      term:
        id: UBERON:0000915
        label: thoracic segment of trunk
  evidence:
  - reference: PMID:25575358
    reference_title: "Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius Vertical Expandable Prosthetic Titanium Rib."
    supports: SUPPORT
    snippet: >-
      Survival rate of the 22 patients was 68%.
    explanation: >-
      Reports 68% survival rate with VEPTR surgical treatment.
  - reference: PMID:25575358
    reference_title: "Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius Vertical Expandable Prosthetic Titanium Rib."
    supports: SUPPORT
    snippet: >-
      The survival rate in JS with surgery was nearly 70% (compared with
      70% to 80% mortality without treatment) with less ventilator dependence.
    explanation: >-
      Demonstrates dramatic improvement in survival with VEPTR surgery
      compared to untreated JATD.
  - reference: PMID:25575358
    reference_title: "Management of Thoracic Insufficiency Syndrome in Patients With Jeune Syndrome Using the 70 mm Radius Vertical Expandable Prosthetic Titanium Rib."
    supports: SUPPORT
    snippet: >-
      Average chest width increased from 121 to 168 mm at follow-up (P<0.001).
    explanation: >-
      Quantifies the significant increase in thoracic dimensions achieved
      by VEPTR expansion surgery.
- name: Renal Management
  description: >
    Monitoring and management of progressive renal cystic disease,
    including dialysis or transplantation for end-stage renal failure.
datasets: []
references:
- reference: DOI:10.1073/pnas.2408551121
  title: Contribution of intraflagellar transport to compartmentalization and
    maintenance of the photoreceptor cell
  findings: []
- reference: DOI:10.1101/2022.03.31.486414
  title: Disease-associated mutations in WDR34 lead to diverse impacts on the
    assembly and function of dynein-2
  findings: []
- reference: DOI:10.1159/000534031
  title: Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected
    Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in
    &lt;i&gt;GRK2:&lt;/i&gt; A Newly Associated Gene for Jeune Syndrome
    Phenotype
  findings: []
- reference: DOI:10.1186/s12920-023-01753-y
  title: Clinical features and genetic analysis of a case series of skeletal
    ciliopathies in a prenatal setting
  findings: []
- reference: DOI:10.1186/s41065-025-00375-x
  title: A novel compound heterozygous mutation in the DYNC2H1 gene in a Chinese
    family with Jeune syndrome
  findings: []
- reference: DOI:10.1371/journal.pgen.1010796
  title: IFT74 variants cause skeletal ciliopathy and motile cilia defects in
    mice and humans
  findings: []
📚

References & Deep Research

References

6
DOI:10.1073/pnas.2408551121
Contribution of intraflagellar transport to compartmentalization and maintenance of the photoreceptor cell
No top-level findings curated for this source.
DOI:10.1101/2022.03.31.486414
Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2
No top-level findings curated for this source.
DOI:10.1159/000534031
Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in &lt;i&gt;GRK2:&lt;/i&gt; A Newly Associated Gene for Jeune Syndrome Phenotype
No top-level findings curated for this source.
DOI:10.1186/s12920-023-01753-y
Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting
No top-level findings curated for this source.
DOI:10.1186/s41065-025-00375-x
A novel compound heterozygous mutation in the DYNC2H1 gene in a Chinese family with Jeune syndrome
No top-level findings curated for this source.
DOI:10.1371/journal.pgen.1010796
IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Jeune Asphyxiating Thoracic Dystrophy
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 32

Key Pathophysiology Nodes

  • Intraflagellar Transport Dysfunction
  • Dynein Motor Complex Deficiency
  • Renal Cystogenesis
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1073/pnas.2408551121
  • DOI:10.1101/2022.03.31.486414
  • DOI:10.1159/000534031
  • DOI:10.1186/s12920-023-01753-y
  • DOI:10.1186/s41065-025-00375-x
  • DOI:10.1371/journal.pgen.1010796
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 17 citations 2026-02-10T07:51:32.624642

Disease Pathophysiology Research Report

Target Disease - Disease Name: Jeune Asphyxiating Thoracic Dystrophy (JATD) / Short-Rib Thoracic Dysplasia (SRTD spectrum) - MONDO ID: MONDO_0018770 (Jeune syndrome) - Category: Mendelian

Pathophysiology overview Jeune asphyxiating thoracic dystrophy is a skeletal ciliopathy in which defects of primary cilia—especially intraflagellar transport (IFT) and the dynein-2 retrograde motor—disrupt morphogen signaling essential for endochondral bone growth, narrowing the thoracic cage and producing life‑threatening respiratory insufficiency. Mechanistic studies show that mutations in dynein-2 subunits (e.g., DYNC2H1, WDR34) and IFT subunits (IFT-A and IFT-B) impair retrograde trafficking, axoneme extension, transition zone integrity, and ciliary localization of signaling components, culminating in defective Hedgehog (Shh/Ihh) pathway activity in chondrocytes and other ciliated epithelia (Shak 2023, Journal of Cell Science, Aug 2023, https://doi.org/10.1101/2022.03.31.486414) (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21). A 2023 PLOS Genetics study extended the gene spectrum to IFT74 and provided cross‑species evidence that perturbations of the tubulin‑transporting IFT-B module cause skeletal and, in some alleles, motile cilia phenotypes affecting mucociliary clearance (Bakey 2023, PLOS Genetics, Jun 2023, https://doi.org/10.1371/journal.pgen.1010796) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). Prenatal case series reinforce that pathogenic variants in DYNC2H1 (dynein-2 heavy chain), IFT172, and WDR19 underlie the short‑rib/narrow‑thorax phenotype observed on ultrasound, with frequent renal involvement (Peng 2023, BMC Medical Genomics, Dec 2023, https://doi.org/10.1186/s12920-023-01753-y) (peng2023clinicalfeaturesand pages 4-7). Beyond IFT per se, newer work implicates disruption of cilia‑based Smoothened accumulation and GRK2‑dependent modulation of Hedgehog/Wnt signaling as a cause of ATD‑like phenotypes, expanding mechanistic models beyond IFT failure (Topçu 2024, Molecular Syndromology, Nov 2024, https://doi.org/10.1159/000534031) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3).

1) Core pathophysiological mechanisms and dysregulated pathways - Defective retrograde IFT via dynein-2: WDR34 disease variants alter dynein‑2 assembly and function, causing defects in axoneme initiation/extension, mislocalization of IFT-B proteins, transition zone (TZ) abnormalities, and reduced Hedgehog signaling; these findings directly link dynein‑2 dysfunction to the skeletal ciliopathy mechanism (Shak 2023, J Cell Sci, Aug 2023, https://doi.org/10.1101/2022.03.31.486414) (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21). - IFT-B cargo/tubulin transport defects: IFT74, the tubulin‑binding IFT-B subunit, is required for primary and motile cilia assembly; biallelic human variants produce Jeune/SRPS‑spectrum skeletal phenotypes and, in exon 2 deletion alleles, motile cilia defects causing mucociliary disease, demonstrating that primary cilium transport insufficiency drives skeletal disease (Bakey 2023, PLOS Genetics, Jun 2023, https://doi.org/10.1371/journal.pgen.1010796) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Hedgehog/Ihh signaling disruption in chondrocytes: Clinical genetics and cellular studies converge on impaired ciliary Hedgehog signaling as a key lesion in JATD; GRK2 loss‑of‑function prevents phosphorylation‑dependent ciliary accumulation of Smoothened and diminishes downstream Hh/Wnt signaling outputs in cartilage development (Topçu 2024, Mol Syndromology, Nov 2024, https://doi.org/10.1159/000534031) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). WDR34 perturbations also compromise Hh signaling, reinforcing this axis (Shak 2023, J Cell Sci) (shak2023diseaseassociatedmutationsin pages 1-4). - Transition zone and cilium integrity: Dynein‑2/IFT mutations perturb TZ integrity and IFT-B localization, consistent with broader defects in ciliary gating and compartmentalization that secondarily impair morphogen trafficking and signaling (Shak 2023, J Cell Sci) (shak2023diseaseassociatedmutationsin pages 1-4).

2) Key molecular players - Genes/proteins with strong evidence in JATD/SRTD spectrum: DYNC2H1 (dynein‑2 heavy chain), WDR34 (DYNC2I2, dynein‑2 intermediate chain), IFT74 (IFT‑B tubulin transport), IFT172 (IFT‑B), WDR19 (IFT144/IFT‑A), and GRK2 (Smoothened/Hh regulation) (Peng 2023; Shak 2023; Bakey 2023; Topçu 2024) (peng2023clinicalfeaturesand pages 4-7, shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28, topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). - Additional dynein‑2/IFT candidates in the broader skeletal ciliopathy literature and clinical series include WDR60 (DYNC2I1), DYNC2LI1, TTC21B/IFT139, IFT43, IFT52, IFT122, IFT140; the gathered recent sources explicitly document WDR19/IFT172/IFT74/ WDR34/DYNC2H1 as active contributors in the period 2023–2024 (Peng 2023; Shak 2023; Bakey 2023) (peng2023clinicalfeaturesand pages 4-7, shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Ciliary signaling/basal body regulators with Jeune overlap: EVC/EVC2 (EvC ciliary complex; positive Hh regulators), KIAA0586/TALPID3, CSPP1—supported by disease-target resources and the Jeune/Joubert overlap; these remain mechanistic context rather than 2023–2024 primary data in our evidence set (OpenTargets MONDO_0018770; context from Topçu 2024) (topcu2024reanalysisofwholeexome pages 1-2). - Cell types: Growth-plate chondrocytes are principal effector cells for thoracic skeletal narrowing; additional ciliated epithelia (airway, renal tubules) are frequently involved clinically and mechanistically in IFT‑related disease (Peng 2023; Bakey 2023) (peng2023clinicalfeaturesand pages 4-7, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Anatomical locations: Thoracic cage/ribs/sternum (skeletal growth plates), pelvis/limbs, kidney (renal tubules), and airway epithelium (Peng 2023; Bakey 2023) (peng2023clinicalfeaturesand pages 4-7, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28).

Key genes and molecular roles (artifact) | HGNC symbol | Protein / complex | Mechanistic role (IFT / dynein-2 / TZ / signaling) | Primary pathway(s) | Key tissues / cell types | Representative evidence (PMID / context) | Source URL | Year | |---|---|---|---|---|---:|---|---:| | DYNC2H1 | Dynein cytoplasmic 2 heavy chain 1 (dynein-2 motor) | Retrograde intraflagellar transport (dynein-2 motor); required for ciliary protein recycling and IFT train retrograde movement | Intraflagellar transport (retrograde), Hedgehog signaling regulation | Growth-plate chondrocytes, respiratory epithelium, renal epithelium | see (peng2023clinicalfeaturesand pages 4-7) | https://doi.org/10.1186/s12920-023-01753-y | 2023 | | WDR34 | Dynein-2 intermediate chain (part of dynein-2 complex) | Dynein-2 assembly and stability; affects axoneme initiation/extension, IFT-B localization and transition zone integrity; impacts Hedgehog signaling | IFT (retrograde), Hedgehog/SHH signaling, PCP | Chondrocytes, kidney, eye (multisystem) | see (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21) | https://doi.org/10.1101/2022.03.31.486414 | 2023 | | WDR60 | Dynein-2 intermediate chain | Structural/intermediate chain of dynein-2; contributes to retrograde IFT and dynein-2 function | IFT (retrograde), Hedgehog signaling | Chondrocytes, ciliated epithelia | see review / context | | | | IFT140 | IFT-A complex subunit | IFT-A component required for retrograde IFT and ciliary protein retrieval; implicated in skeletal ciliopathies with kidney involvement | IFT (retrograde), Hedgehog signaling | Chondrocytes, renal epithelium | see review / context | | | | IFT172 | IFT-B associated subunit (IFT-B peripheral) | IFT-B component required for anterograde IFT and ciliary assembly; mutations linked to SRTD/Jeune phenotypes | IFT (anterograde/assembly), Hedgehog signaling | Chondrocytes, fetal skeletal tissues, renal epithelium | see (peng2023clinicalfeaturesand pages 4-7) | https://doi.org/10.1186/s12920-023-01753-y | 2023 | | IFT74 | IFT-B subunit (tubulin-binding module) | Tubulin carriage for axoneme assembly; required for primary and motile cilia assembly — loss causes skeletal ciliopathy and motile cilia defects | IFT (tubulin transport), ciliogenesis, Hedgehog signaling | Chondrocytes (growth plate), motile ciliated epithelia (airways) | see (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28) | https://doi.org/10.1371/journal.pgen.1010796 | 2023 | | WDR19 | IFT-A associated WD-repeat protein (IFT144/WDR19) | IFT-A component required for retrograde transport and ciliary function; linked to SRTD/renal phenotypes | IFT (retrograde), Hedgehog signaling | Chondrocytes, renal epithelium | see (peng2023clinicalfeaturesand pages 4-7) | https://doi.org/10.1186/s12920-023-01753-y | 2023 | | TTC21B (IFT139) | IFT-A complex subunit (TTC21B/IFT139) | IFT-A structural subunit; required for retrograde trafficking and TZ interactions | IFT (retrograde), Hedgehog signaling | Chondrocytes, renal epithelium | see review / context | | | | IFT43 | IFT-A subunit | Structural IFT-A component; contributes to IFT-A function and ciliary trafficking | IFT (retrograde), ciliogenesis | Ciliated cell types (including chondrocytes' primary cilia) | see review / context | | | | IFT52 | IFT-B core subunit | IFT-B core component required for anterograde transport of IFT trains and cargo | IFT (anterograde), ciliogenesis | Chondrocytes, photoreceptors, ciliated epithelia | see review / context | | | | IFT122 | IFT-A subunit | IFT-A complex member; implicated in retrograde IFT and associated with renal/skeletal ciliopathies | IFT (retrograde), Hedgehog signaling | Growth plate chondrocytes, kidney | see review / context | | | | GRK2 | G protein-coupled receptor kinase 2 | Modulates cilia-based Hedgehog signaling (Smoothened phosphorylation/accumulation); loss impairs Hh/Wnt signaling in chondrocytes leading to ATD phenotype | Hedgehog (Smoothened regulation), Wnt signaling modulation | Chondrocytes (skeletal development) | see (topcu2024reanalysisofwholeexome pages 1-2) | https://doi.org/10.1159/000534031 | 2024 | | EVC / EVC2 | EvC ciliary complex (basal body / EvC zone) | Positive regulators of Hedgehog signaling at the ciliary base (EvC complex); mutations perturb Hh-dependent skeletal development | Hedgehog signaling | Chondrocytes, skeletal tissues | see review / context | | | | KIAA0586 (TALPID3) | Centrosomal / basal body protein (TALPID3) | Basal-body / ciliogenesis regulator required for cilium assembly and Hedgehog pathway organization | Ciliogenesis, Hedgehog signaling | Neural and skeletal progenitors, chondrocytes | see review / context | | | | CSPP1 | Centrosome and spindle pole associated protein 1 | Centriolar / ciliogenesis factor; implicated in Joubert syndrome with Jeune overlap (ciliary dysfunction affecting development) | Ciliogenesis, microtubule organization, Hedgehog signaling | Neural progenitors, chondrocytes | see review / context | | |

Table: Table summarizing genes implicated in Jeune/asphyxiating thoracic dysplasia, their molecular roles and primary evidence; includes context citations to recent 2023–2024 studies used to populate the table.

3) Biological processes (for GO-like annotation; labels) - Intraflagellar transport (retrograde and anterograde) and dynein-2 motor function (Shak 2023; Bakey 2023) (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Cilium assembly/axoneme extension and ciliary protein localization (Shak 2023; Bakey 2023) (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6). - Smoothened/Hedgehog signaling pathway in chondrocyte proliferation/differentiation; Hh/Wnt crosstalk (Topçu 2024; Shak 2023) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3, shak2023diseaseassociatedmutationsin pages 1-4). - Transition zone organization and ciliary compartmentalization (Shak 2023) (shak2023diseaseassociatedmutationsin pages 1-4).

4) Cellular components - Primary cilium (axoneme) and ciliary membrane; IFT trains (A/B); dynein‑2 motor complex (Shak 2023; Bakey 2023) (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6). - Transition zone at the ciliary base (Shak 2023) (shak2023diseaseassociatedmutationsin pages 1-4). - Basal body/centrosome and EvC subdomain (context; supported by Jeune/EVC literature referenced in recent case analysis) (Topçu 2024) (topcu2024reanalysisofwholeexome pages 1-2).

5) Disease progression (molecular-to-clinical sequence) - Initiation: Biallelic pathogenic variants in dynein‑2 (e.g., DYNC2H1, WDR34) or IFT subunits (IFT74, IFT172, WDR19) impair IFT and cilium integrity, including axoneme extension and TZ function (Shak 2023; Bakey 2023; Peng 2023) (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, peng2023clinicalfeaturesand pages 4-7). - Signaling disruption: Reduced ciliary trafficking of Hedgehog components (e.g., Smoothened), attenuated Hh/Ihh readouts, and altered Wnt signaling in chondrocytes (Topçu 2024; Shak 2023) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3, shak2023diseaseassociatedmutationsin pages 1-4). - Cellular consequences: Impaired chondrocyte proliferation/differentiation and disordered growth‑plate architecture limit endochondral ossification of ribs/sternum, producing a shortened, narrow thoracic cage (Topçu 2024; Peng 2023) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3, peng2023clinicalfeaturesand pages 4-7). - System involvement: Depending on the gene/allele, defects also affect motile cilia (in some IFT74 alleles) and non‑skeletal primary cilia in kidney/airway, explaining renal and respiratory morbidity beyond rib hypoplasia (Bakey 2023; Peng 2023) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28, peng2023clinicalfeaturesand pages 4-7). - Clinical outcome: Neonatal respiratory insufficiency from thoracic restriction is common; prenatal ultrasound frequently shows narrow thorax/short long bones; renal dilation/cysts may be present (Peng 2023) (peng2023clinicalfeaturesand pages 4-7).

6) Phenotypic manifestations and their mechanistic links - Skeletal: Short ribs, narrow bell‑shaped thorax, short long bones, hypoplastic iliac wings; these result from impaired Hh/Ihh signaling in chondrocytes secondary to IFT/dynein‑2 dysfunction (Topçu 2024; Shak 2023; Peng 2023) (topcu2024reanalysisofwholeexome pages 2-3, shak2023diseaseassociatedmutationsin pages 1-4, peng2023clinicalfeaturesand pages 4-7). - Respiratory: Neonatal respiratory distress due to restrictive thoracic cage; in some IFT74 alleles, motile cilia dysfunction contributes to mucociliary impairment (Bakey 2023) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Renal/hepatic/ocular: Renal enlargement or cystic changes are reported prenatally in SRTD cases; ocular and hepatic involvement are recognized in Jeune spectrum, reflecting multi‑organ primary cilia roles (Peng 2023; Topçu 2024) (peng2023clinicalfeaturesand pages 4-7, topcu2024reanalysisofwholeexome pages 2-3).

Recent developments (2023–2024) - Gene discovery/expansion: IFT74 established as a skeletal ciliopathy gene with allele‑specific primary vs motile cilia consequences (Bakey 2023, PLOS Genetics, Jun 2023, https://doi.org/10.1371/journal.pgen.1010796) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). GRK2 implicated in Jeune‑like phenotype via impaired ciliary Smoothened/Hh and Wnt signaling, broadening mechanisms beyond core IFT (Topçu 2024, Mol Syndromology, Nov 2024, https://doi.org/10.1159/000534031) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). - Mechanistic precision: Quantitative proteomics and rescue studies define how specific WDR34 variants variably disrupt dynein‑2 assembly, IFT‑B localization, transition zone integrity, and Hh signaling, explaining genotype‑phenotype heterogeneity (Shak 2023, J Cell Sci, Aug 2023, https://doi.org/10.1101/2022.03.31.486414) (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21). - Prenatal diagnostics: A 2023 prenatal case series demonstrates exome sequencing utility for differentiating lethal SRPS from non‑lethal Jeune/SRTD, identifying novel DYNC2H1, IFT172 and WDR19 variants with ultrasound correlation (Peng 2023, BMC Medical Genomics, Dec 2023, https://doi.org/10.1186/s12920-023-01753-y) (peng2023clinicalfeaturesand pages 4-7).

Current applications and real‑world implementations - Genomic diagnostics: Clinical exome sequencing and reanalysis enable molecular diagnosis and gene discovery in JATD/SRTD (Peng 2023; Topçu 2024) (peng2023clinicalfeaturesand pages 4-7, topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). - Mechanism‑informed counseling: Identification of dynein‑2/IFT mutations supports prognosis of extra‑skeletal risks (e.g., renal disease) and informs reproductive counseling (Peng 2023) (peng2023clinicalfeaturesand pages 4-7). - Therapeutic insight (preclinical): While not disease‑specific, acute IFT perturbation studies in photoreceptors reveal specialized disposal pathways and suggest transport‑module‑specific interventions; this underscores potential for targeting ciliary transport or signaling nodes, though translation to JATD remains future work (Lewis 2024, PNAS, Aug 2024, https://doi.org/10.1073/pnas.2408551121) ( not available; note: our gathered evidence provides the mechanistic theme without direct citation id for this item, so we do not rely on it for major claims).

Expert opinions and analysis - “Disease‑associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein‑2,” highlighting that variant‑specific dynein‑2 defects differentially affect cilia formation, IFT‑B localization, TZ integrity, and Hedgehog signaling, a mechanistic basis for phenotypic diversity in Jeune/SRTD (Shak 2023, J Cell Sci, Aug 2023, https://doi.org/10.1101/2022.03.31.486414) (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21). - “IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans,” providing authoritative confirmation that IFT‑B tubulin transport deficits are sufficient to produce Jeune/SRPS‑spectrum disease and, in some alleles, airway disease, unifying primary and motile cilia pathology within the skeletal ciliopathy framework (Bakey 2023, PLOS Genetics, Jun 2023, https://doi.org/10.1371/journal.pgen.1010796) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28).

Relevant statistics and data (recent studies) - Prenatal series (n=4 fetuses) with SRTD/SRPS‑spectrum: all had narrow thorax and short long bones on ultrasound; exome sequencing identified novel pathogenic/likely pathogenic variants in DYNC2H1 (three variants across cases), IFT172 (splice region), and WDR19 (missense), with renal findings in some cases (Peng 2023, BMC Medical Genomics, Dec 2023, https://doi.org/10.1186/s12920-023-01753-y) (peng2023clinicalfeaturesand pages 4-7). Larger population mortality statistics specific to JATD were not reported in the 2023–2024 sources curated here.

Ontology‑style annotations (labels; curated from evidence and domain standards) - Genes/proteins (HGNC symbols): DYNC2H1; WDR34; IFT74; IFT172; WDR19; GRK2; plus context genes WDR60, DYNC2LI1, TTC21B, IFT43, IFT52, IFT122, IFT140, EVC, EVC2, KIAA0586, CSPP1 (peng2023clinicalfeaturesand pages 4-7, shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28, topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). - Biological processes (GO labels): intraflagellar transport; cilium assembly/axoneme extension; Smoothened/Hedgehog signaling; ciliary protein localization; transition zone organization (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28, topcu2024reanalysisofwholeexome pages 1-2). - Cellular components: primary cilium (axoneme), IFT trains (A/B), dynein‑2 complex, transition zone, basal body/EvC zone (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, topcu2024reanalysisofwholeexome pages 1-2). - Cell types (CL labels): growth‑plate chondrocytes; airway epithelial cells; renal tubular epithelial cells (peng2023clinicalfeaturesand pages 4-7, bakey2023ift74variantscause pages 3-6). - Anatomical locations (UBERON labels): thoracic cage/ribs/sternum; pelvis/long bones; kidney; airway/respiratory tract (peng2023clinicalfeaturesand pages 4-7, bakey2023ift74variantscause pages 3-6). - Chemical entities (CHEBI labels; signaling context): Smoothened agonism/phosphorylation state (protein; signaling lipid co‑factors are implicated in Hh biology but were not directly evaluated in the 2023–2024 sources used here) (topcu2024reanalysisofwholeexome pages 1-2).

Evidence items with PMIDs and URLs (selection) - Peng 2023. BMC Medical Genomics. Clinical prenatal series linking DYNC2H1/IFT172/WDR19 to SRTD. PMID: not provided in excerpt; DOI: 10.1186/s12920-023-01753-y; URL: https://doi.org/10.1186/s12920-023-01753-y (Dec 2023) (peng2023clinicalfeaturesand pages 4-7). - Shak 2023. Journal of Cell Science. Functional analysis of WDR34 variants defining dynein‑2/IFT/TZ/Hh defects. PMID: not provided in excerpt; DOI: 10.1101/2022.03.31.486414; URL: https://doi.org/10.1101/2022.03.31.486414 (Aug 2023) (shak2023diseaseassociatedmutationsin pages 1-4, shak2023diseaseassociatedmutationsin pages 21-21). - Bakey 2023. PLOS Genetics. IFT74 variants causing skeletal ciliopathy and motile cilia defects; human and mouse data. PMID: not provided in excerpt; DOI: 10.1371/journal.pgen.1010796; URL: https://doi.org/10.1371/journal.pgen.1010796 (Jun 2023) (bakey2023ift74variantscause pages 3-6, bakey2023ift74variantscause pages 27-28). - Topçu 2024. Molecular Syndromology. GRK2 variant expanding Jeune pathophysiology via cilia‑based Hh/Wnt signaling. PMID: not provided in excerpt; DOI: 10.1159/000534031; URL: https://doi.org/10.1159/000534031 (Nov 2024) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3). - Additional context on DYNC2H1 variant spectrum and diagnostic yield in recent family/case reports is concordant with the above mechanisms (Xiong 2025; Hereditas; Jan 2025; https://doi.org/10.1186/s41065-025-00375-x) (xiong2025anovelcompound pages 8-8). While beyond the 2024 priority window, it supports the centrality of dynein‑2/retrograde IFT in Jeune/SRTD pathogenesis.

Direct supporting quotes - “Disease‑associated mutations in WDR34 are found to have diverse impacts on ciliogenesis and cilia function… initiation and extension of the axoneme, IFT‑B protein localization, transition zone integrity, and Hedgehog signalling were also affected.” (Shak 2023, J Cell Sci, Aug 2023, https://doi.org/10.1101/2022.03.31.486414) (shak2023diseaseassociatedmutationsin pages 1-4). - “IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.” (Bakey 2023, PLOS Genetics, Jun 2023, https://doi.org/10.1371/journal.pgen.1010796) (bakey2023ift74variantscause pages 3-6). - Prenatal SRTD cases: “The major and common ultrasound anomalies… included short long bones of the limbs and narrow thorax… Exome sequencing revealed… variants in the DYNC2H1 gene… IFT172… and WDR19.” (Peng 2023, BMC Med Genomics, Dec 2023, https://doi.org/10.1186/s12920-023-01753-y) (peng2023clinicalfeaturesand pages 4-7). - GRK2 mechanism: case‑level re‑analysis revealed a likely pathogenic GRK2 variant and the report notes disturbed “cilia‑based signaling of Hedgehog pathway as well as Wnt signaling,” with ATD phenotype without IFT subcomplex impairment (Topçu 2024, Mol Syndromology, Nov 2024, https://doi.org/10.1159/000534031) (topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3).

Limitations and gaps - Precise population‑level mortality rates and organ involvement frequencies specific to genetically confirmed JATD were not provided in the 2023–2024 sources synthesized here. Larger registries and meta‑analyses will be needed for robust epidemiologic statistics; nonetheless, the prenatal and functional studies strongly support the mechanistic framework above (peng2023clinicalfeaturesand pages 4-7, shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6).

Conclusion JATD is driven by primary cilium dysfunction centered on IFT and dynein‑2 retrograde transport, leading to impaired Hedgehog signaling in growth‑plate chondrocytes and a characteristic thoracic skeletal restriction. Recent work refined this model by: (i) demonstrating variant‑specific dynein‑2 assembly and TZ/IFT‑B defects (WDR34), (ii) establishing IFT74 as a tubulin‑transport subunit whose loss produces Jeune/SRPS‑spectrum skeletal disease and, in some alleles, motile cilia pathology, and (iii) implicating cilia‑based Hh/Wnt control via GRK2 as an alternative route to the Jeune phenotype. These insights, together with prenatal exome diagnostics, delineate a coherent molecular‑to‑clinical sequence and highlight avenues for mechanism‑informed counseling and future therapy development (Shak 2023; Bakey 2023; Peng 2023; Topçu 2024) (shak2023diseaseassociatedmutationsin pages 1-4, bakey2023ift74variantscause pages 3-6, peng2023clinicalfeaturesand pages 4-7, topcu2024reanalysisofwholeexome pages 1-2, topcu2024reanalysisofwholeexome pages 2-3, bakey2023ift74variantscause pages 27-28).

References

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