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Jeune Asphyxiating Thoracic Dystrophy

Disease Pathophysiology Research Report

2026-02-10
Falcon MONDO:0018770 Model: Edison Scientific Literature 17 citations

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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  3. (bakey2023ift74variantscause pages 3-6): Zeineb Bakey, Oscar A. Cabrera, Julia Hoefele, Dinu Antony, Kaman Wu, Michael W. Stuck, Dimitra Micha, Thibaut Eguether, Abigail O. Smith, Nicole N. van der Wel, Matias Wagner, Lara Strittmatter, Philip L. Beales, Julie A. Jonassen, Isabelle Thiffault, Maxime Cadieux-Dion, Laura Boyes, Saba Sharif, Beyhan Tüysüz, Desiree Dunstheimer, Hans W. M. Niessen, William Devine, Cecilia W. Lo, Hannah M. Mitchison, Miriam Schmidts, and Gregory J. Pazour. Ift74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans. PLOS Genetics, 19:e1010796, Jun 2023. URL: https://doi.org/10.1371/journal.pgen.1010796, doi:10.1371/journal.pgen.1010796. This article has 24 citations and is from a domain leading peer-reviewed journal.

  4. (bakey2023ift74variantscause pages 27-28): Zeineb Bakey, Oscar A. Cabrera, Julia Hoefele, Dinu Antony, Kaman Wu, Michael W. Stuck, Dimitra Micha, Thibaut Eguether, Abigail O. Smith, Nicole N. van der Wel, Matias Wagner, Lara Strittmatter, Philip L. Beales, Julie A. Jonassen, Isabelle Thiffault, Maxime Cadieux-Dion, Laura Boyes, Saba Sharif, Beyhan Tüysüz, Desiree Dunstheimer, Hans W. M. Niessen, William Devine, Cecilia W. Lo, Hannah M. Mitchison, Miriam Schmidts, and Gregory J. Pazour. Ift74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans. PLOS Genetics, 19:e1010796, Jun 2023. URL: https://doi.org/10.1371/journal.pgen.1010796, doi:10.1371/journal.pgen.1010796. This article has 24 citations and is from a domain leading peer-reviewed journal.

  5. (peng2023clinicalfeaturesand pages 4-7): Ying Peng, Lin Zhou, Jing Chen, Xiaoliang Huang, Jialun Pang, Jing Liu, Wanglan Tang, Shuting Yang, Changbiao Liang, and Wanqin Xie. Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting. BMC Medical Genomics, Dec 2023. URL: https://doi.org/10.1186/s12920-023-01753-y, doi:10.1186/s12920-023-01753-y. This article has 2 citations and is from a peer-reviewed journal.

  6. (topcu2024reanalysisofwholeexome pages 1-2): V. Topçu, Said Furkan Yıldırım, and Husnu Mutlu Turan. Reanalysis of whole-exome sequencing data of an infant with suspected diagnosis of jeune syndrome revealed a likely pathogenic variant in grk2: a newly associated gene for jeune syndrome phenotype. Molecular Syndromology, 15:119-124, Nov 2024. URL: https://doi.org/10.1159/000534031, doi:10.1159/000534031. This article has 1 citations and is from a peer-reviewed journal.

  7. (topcu2024reanalysisofwholeexome pages 2-3): V. Topçu, Said Furkan Yıldırım, and Husnu Mutlu Turan. Reanalysis of whole-exome sequencing data of an infant with suspected diagnosis of jeune syndrome revealed a likely pathogenic variant in grk2: a newly associated gene for jeune syndrome phenotype. Molecular Syndromology, 15:119-124, Nov 2024. URL: https://doi.org/10.1159/000534031, doi:10.1159/000534031. This article has 1 citations and is from a peer-reviewed journal.

  8. (xiong2025anovelcompound pages 8-8): Sujie Xiong, Guangyao Hu, Yao Zhou, Fei Sun, and Yanlin Ma. A novel compound heterozygous mutation in the dync2h1 gene in a chinese family with jeune syndrome. Hereditas, Jan 2025. URL: https://doi.org/10.1186/s41065-025-00375-x, doi:10.1186/s41065-025-00375-x. This article has 1 citations and is from a peer-reviewed journal.