Short-rib polydactyly syndromes (SRPS) are a group of autosomal recessive lethal skeletal ciliopathies characterized by extremely short ribs, narrow thorax, short limbs, polydactyly, and multiorgan abnormalities. They represent the severe end of the short-rib thoracic dysplasia spectrum, with Jeune syndrome at the milder end. Multiple genetic subtypes are recognized, all involving genes required for intraflagellar transport or ciliogenesis. Death typically occurs in the perinatal period from respiratory insufficiency.
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name: Short-Rib Polydactyly Syndrome
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
description: >
Short-rib polydactyly syndromes (SRPS) are a group of autosomal recessive lethal
skeletal ciliopathies characterized by extremely short ribs, narrow thorax,
short limbs, polydactyly, and multiorgan abnormalities. They represent the
severe end of the short-rib thoracic dysplasia spectrum, with Jeune syndrome
at the milder end. Multiple genetic subtypes are recognized, all involving
genes required for intraflagellar transport or ciliogenesis. Death typically
occurs in the perinatal period from respiratory insufficiency.
disease_term:
preferred_term: Short rib-polydactyly syndrome
term:
id: MONDO:0015461
label: short rib-polydactyly syndrome
parents:
- Ciliopathies
- Short-Rib Dysplasias
inheritance:
- name: Autosomal Recessive
description: >
Autosomal recessive inheritance. Genetic heterogeneity with mutations
in multiple ciliary transport genes.
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: PARTIAL
snippet: >-
Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an
autosomal-recessive chondrodysplasia characterized by short ribs, a narrow
thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal
malformations and is lethal in the perinatal period.
explanation: "Confirms autosomal recessive inheritance of SRP type III."
prevalence:
- population: Published literature worldwide
percentage: Extremely rare; precise population prevalence not established
notes: >-
PMID-indexed literature consistently describes classic short-rib
polydactyly syndromes as lethal perinatal skeletal ciliopathies reported in
small family and fetal series rather than robust population registries.
evidence:
- reference: PMID:24183449
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period."
explanation: This human genetics report confirms the syndrome's perinatal lethality and extreme rarity in clinical series.
- reference: PMID:25313840
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Short rib syndrome (SRS) is one of the lethal osteochondrodysplasias and has been traditionally divided into four types (I—Saldino-Noonan, II—Majewski, III—Verma-Naumoff, and IV—Beemer-Langer)."
explanation: This pathology review supports that the classic SRPS entities are rare lethal osteochondrodysplasias rather than common, registry-defined disorders.
pathophysiology:
- name: Intraflagellar Transport and Ciliogenesis Defects
conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
description: >
SRPS are caused by mutations in genes encoding components of the
intraflagellar transport (IFT) machinery, dynein motor complexes,
and basal body proteins. These mutations disrupt primary cilium
assembly and maintenance, producing structurally abnormal cilia
(shortened, bulbous tips) or reduced cilia number.
biological_processes:
- preferred_term: Intraflagellar Transport
term:
id: GO:0042073
label: intraciliary transport
- 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:22791528
reference_title: "Ciliary disorder of the skeleton."
supports: SUPPORT
snippet: >-
10 different genes have been identified as responsible for seven "skeletal"
ciliopathies. Mutations have been identified in dynein motor (DYNC2H1), in
intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19,
and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and
EVC2)
explanation: "Comprehensive overview showing mutations across dynein, IFT, and basal body genes."
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
snippet: >-
absence of functional full-length NEK1 severely reduces cilia number and
alters ciliar morphology in vivo
explanation: "Demonstrates that NEK1 loss-of-function directly impairs ciliogenesis."
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
primary cilia in WDR34 mutant fibroblasts were significantly shorter than
normal and had a bulbous tip
explanation: "Shows direct ciliary structural abnormalities in WDR34-mutant cells."
- 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 role in ciliary generation and maintenance."
- name: Hedgehog Signaling Disruption in Skeletal Development
conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
description: >
Primary cilia are essential for transduction of Hedgehog signaling,
which is critical for endochondral ossification and limb patterning.
Ciliary dysfunction from IFT/dynein defects disrupts Hedgehog-dependent
chondrocyte proliferation and differentiation, leading to severe skeletal
shortening and polydactyly. The skeletal and organ phenotypes in SRPS
are more severe than in Jeune syndrome, reflecting a greater degree of
ciliary dysfunction.
biological_processes:
- preferred_term: Hedgehog Signaling
term:
id: GO:0007224
label: smoothened signaling pathway
cell_types:
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
evidence:
- reference: PMID:22791528
reference_title: "Ciliary disorder of the skeleton."
supports: PARTIAL
snippet: >-
primary cilia play a vital role in transduction of signals in the hedgehog
pathway that is especially important in skeletal development
explanation: "Establishes the role of primary cilia and hedgehog signaling in skeletal ciliopathies."
phenotypes:
- name: Extremely Short Ribs
description: >
Severely shortened ribs leading to a markedly constricted thorax.
More severe than in Jeune syndrome, causing perinatal lethality.
phenotype_term:
preferred_term: Short ribs
term:
id: HP:0000773
label: Short ribs
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
characterized by short ribs, a narrow thorax, short long bones, an abnormal
acetabulum, and numerous extraskeletal malformations and is lethal in the
perinatal period
explanation: "Describes the cardinal skeletal features of SRP type III including short ribs and perinatal lethality."
- reference: PMID:19442771
reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
supports: PARTIAL
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: "Confirms short ribs as characteristic of the ATD-SRP spectrum."
- name: Narrow Thorax
description: >
Extremely narrow thoracic cage incompatible with postnatal
respiratory function.
phenotype_term:
preferred_term: Narrow chest
term:
id: HP:0000774
label: Narrow chest
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
characterized by short ribs, a narrow thorax, short long bones
explanation: "Narrow thorax is a defining feature of SRP type III."
- name: Polydactyly
description: >
Polydactyly, typically postaxial, is a cardinal feature present
in most SRPS subtypes.
phenotype_term:
preferred_term: Polydactyly
term:
id: HP:0010442
label: Polydactyly
evidence:
- reference: PMID:19442771
reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
supports: PARTIAL
snippet: >-
short ribs and a narrow thorax, short long bones, inconstant polydactyly
explanation: "Polydactyly is a variable but recognized feature in the ATD-SRP spectrum."
- name: Severe Limb Shortening
description: >
Severe shortening of long bones (micromelia) more pronounced
than in Jeune syndrome.
phenotype_term:
preferred_term: Limb undergrowth
term:
id: HP:0009826
label: Limb undergrowth
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
characterized by short ribs, a narrow thorax, short long bones
explanation: "Short long bones are part of the defining phenotype."
- name: Renal Cystic Disease
description: >
Renal cystic dysplasia as part of the multiorgan ciliopathy
phenotype.
phenotype_term:
preferred_term: Renal cyst
term:
id: HP:0000107
label: Renal cyst
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: NO_EVIDENCE
snippet: >-
numerous extraskeletal malformations
explanation: "Renal cystic disease is among the extraskeletal malformations in SRP."
- name: Cardiovascular Defects
description: >
Congenital heart defects including transposition of great vessels,
atrioventricular canal defects, and other structural anomalies.
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
- name: Polyhydramnios
description: >
Polyhydramnios is frequently observed prenatally and may be
the first clinical clue.
phenotype_term:
preferred_term: Polyhydramnios
term:
id: HP:0001561
label: Polyhydramnios
genetic:
- name: DYNC2H1 Mutations (SRP Type III/Verma-Naumoff)
association: Causative
notes: >
Biallelic mutations in DYNC2H1, the most common cause of both
JATD and SRP type III. SRP type III (Verma-Naumoff) and JATD
are now considered variants of a single disorder, with SRP
representing the severe end.
evidence:
- reference: PMID:19442771
reference_title: "DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III."
supports: PARTIAL
snippet: >-
we conclude that ATD and SRP type III are variants of a single disorder
belonging to the ciliopathy group
explanation: "Landmark paper establishing that DYNC2H1 mutations cause both ATD and SRP type III, proving they are a single spectrum."
- 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. Compound heterozygosity for DYNC2H1
mutations was also identified in four additional families
explanation: "Identifies DYNC2H1 mutations in both homozygous and compound heterozygous states."
- name: NEK1 Mutations (SRP Type II/Majewski)
association: Causative
notes: >
Biallelic mutations in NEK1, encoding a kinase involved in
ciliogenesis. Associated with SRP type II (Majewski type),
characterized by disproportionately short tibiae and
preaxial/postaxial polydactyly.
evidence:
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
snippet: >-
We used homozygosity mapping in two families with autosomal-recessive short-rib
polydactyly syndrome Majewski type to identify mutations in NEK1 as an
underlying cause of this lethal osteochondrodysplasia
explanation: "Discovery paper identifying NEK1 as the cause of SRP Majewski type."
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: SUPPORT
snippet: >-
NEK1 encodes a serine/threonine kinase with proposed function in DNA
double-strand repair, neuronal development, and coordination of
cell-cycle-associated ciliogenesis
explanation: "Characterizes NEK1 function including its role in ciliogenesis."
- reference: PMID:21211617
reference_title: "NEK1 mutations cause short-rib polydactyly syndrome type majewski."
supports: PARTIAL
snippet: >-
We further substantiate a proposed digenic diallelic inheritance of
ciliopathies by the identification of heterozygous mutations in NEK1 and
DYNC2H1 in an additional family
explanation: "Reports digenic inheritance involving NEK1 and DYNC2H1, suggesting oligogenic complexity."
- name: WDR34 Mutations (SRP Type III)
association: Causative
notes: >
Biallelic mutations in WDR34, encoding a WD repeat protein
involved in ciliary function and NF-kappaB pathway regulation.
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
homozygosity for three missense mutations in WDR34 were found in three
independent families, as well as compound heterozygosity for mutations in one
family
explanation: "Identifies WDR34 mutations in multiple SRP type III families."
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
This report expands on the pathogenesis of SRP type III and demonstrates that a
regulator of the NF-κB activation pathway is involved in the pathogenesis of the
skeletal ciliopathies
explanation: "Reveals unexpected link between NF-kappaB signaling and ciliary function in SRP."
- name: IFT80 Mutations
association: Causative
notes: >
Biallelic mutations in IFT80, a component of the IFT-B complex.
Can cause both JATD and SRP phenotypes.
evidence:
- reference: PMID:19648123
reference_title: "Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum."
supports: SUPPORT
snippet: >-
mutations in IFT80 can also be responsible for a lethal form of SRP and provide
the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum
explanation: "Demonstrates that IFT80 mutations can cause both lethal SRP and milder JATD, establishing the Jeune-Verma-Naumoff spectrum."
- reference: PMID:19648123
reference_title: "Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum."
supports: SUPPORT
snippet: >-
Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion
in exon 8 (G241R) in only one SRP case closely related to the type III phenotype
explanation: "Identifies specific IFT80 mutation in an SRP type III case."
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
description: >-
Short-rib polydactyly syndrome is diagnosed prenatally or at birth from the
severe short-rib/narrow-thorax phenotype with polydactyly and characteristic
radiographic findings, and is confirmed by molecular genetic testing of the
skeletal-ciliopathy genes. It is differentiated within the short-rib
polydactyly group from milder ciliopathies such as Jeune ATD and Ellis-van
Creveld syndrome; most cases are perinatally lethal.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:22791528
reference_title: "Ciliary disorder of the skeleton."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the short rib-polydactyly group (SRPs) that includes Verma-Naumoff syndrome (SRP type III), Majewski syndrome (SRP type II), Jeune syndrome (ATD), as well as Ellis-van Creveld syndrome (EVC), the Sensenbrenner syndrome, and, finally, Weyers acrofacial dysostosis."
explanation: >-
Defines the short-rib-polydactyly group and its differential diagnosis
within the skeletal ciliopathies.
- reference: PMID:22791528
reference_title: "Ciliary disorder of the skeleton."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations have been identified in dynein motor (DYNC2H1), in intraflagellar transport (IFT) complexes (IFT80, IFT122, IFT43, WDR35, WDR19, and TTC21B) as well as in genes responsible for the basal body (NEK1, EVC, and EVC2)."
explanation: >-
Supports the panel of skeletal-ciliopathy genes used for molecular
diagnosis of short-rib polydactyly syndromes.
treatments:
- name: Supportive Care
description: >
SRPS are typically lethal in the perinatal period. Management
is primarily supportive with palliative care.
evidence:
- reference: PMID:24183449
reference_title: "WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia."
supports: SUPPORT
snippet: >-
lethal in the perinatal period
explanation: "Perinatal lethality limits treatment to supportive and palliative care."
datasets: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Short-Rib Polydactyly Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Disease Pathophysiology Research Report: Short-Rib Polydactyly Syndrome (SRPS) / Short-Rib Thoracic Dysplasia (SRTD)
Target Disease - Disease Name: Short-Rib Polydactyly Syndrome (SRPS) / Short-Rib Thoracic Dysplasia (SRTD) - MONDO ID: Not confidently resolved here; SRPS/SRTD are classified within skeletal ciliopathies in current nosology. Please verify MONDO mapping during curation. - Category: Mendelian (autosomal recessive)
Pathophysiology summary Short-Rib Polydactyly Syndrome and the broader SRTD spectrum are skeletal ciliopathies caused by dysfunction of the primary cilium, most often due to variants in intraflagellar transport (IFT) machinery (IFT-A, IFT-B) or the retrograde IFT motor dynein-2. Disrupted ciliary trafficking perturbs Hedgehog (Hh) signaling in limb bud mesenchyme and growth-plate chondrocytes, leading to abnormal skeletal patterning (polydactyly) and chondrodysplasia with thoracic insufficiency, and extends to kidney and retinal phenotypes in overlapping syndromes (e.g., Mainzer–Saldino, Jeune). DYNC2H1 (dynein-2 heavy chain) is a major genetic cause; IFT140/IFT-A defects model short-rib phenotypes with ciliation loss and Hh pathway disruption. Prenatal diagnosis increasingly combines systematic ultrasound with exome sequencing to resolve the high genetic heterogeneity of lethal skeletal dysplasias. (xiong2025anovelcompound pages 8-8, francis2023autonomousandnoncell pages 16-20, getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, francis2023autonomousandnoncell pages 20-24)
1) Core Pathophysiology - Primary mechanisms: Defective intraflagellar transport (anterograde IFT-B and retrograde IFT-A/dynein-2) compromises ciliary structure and signaling competence. In limb and cartilage lineages, this dysregulates Sonic/Ihh signaling required for digit number/patterning and growth-plate proliferation–hypertrophy transitions, producing polydactyly and severe thoracic and long-bone shortening. Kidney tubule and retinal photoreceptor cilia involvement explains cystic kidney disease and retinal degeneration in overlapping phenotypes. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Evidence: “Ift80 and ift172 models… exhibited severe limb deformities, polydactyly… and ciliogenesis defects… implicating cilia-dependent signaling (Hedgehog) in skeletal outcomes.” bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18) - Evidence: Ift140 mutant analyses show “low incidence of ciliation” and “disrupted cilia-transduced Shh signaling” with thoracic dystrophy and polydactyly in mice. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Dysregulated pathways: Hedgehog signaling (Shh in limb bud; Ihh in growth plate) is primary; IFT dysfunction can variably modulate Hh outputs in vivo. Additional contributions from Wnt and cilia-associated microtubule modifications (e.g., tubulin polyglutamylation) are implicated. (getwan2020crisprcas9targetingttc30a pages 16-18) - Affected cellular processes: Ciliogenesis, intraciliary cargo transport (anterograde/retrograde), ciliary maintenance, signal transduction; chondrocyte proliferation/differentiation; epithelial polarity in kidney tubules. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)
2) Key Molecular Players - Genes/Proteins (HGNC): DYNC2H1 (dynein-2 heavy chain), DYNC2LI1, WDR60, WDR34, IFT140, WDR19/IFT144, WDR35/IFT121, TTC21B/IFT139, IFT172, IFT80, IFT52, TRAF3IP1/IFT54, IFT43, IFT22, NEK1. Roles span dynein-2 motor assembly/function and IFT-A/B particle integrity. (getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, xiong2025anovelcompound pages 8-8) - Expert/clinical emphasis: DYNC2H1 is a recurrent cause for SRTD/SRPS; compound heterozygous variants are common in severe prenatal/infantile cases. Front-line genomics (WES/RNA-seq) resolves diverse variant classes. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Quantitative note: DYNC2H1 accounts for a large subset of SRTD3; a 2022 overview notes it “cause[s] SRTD3” and is cited in >50% of such cases in compilations. (markova2022сlinicalandgenetic pages 9-11) - Chemical entities (CHEBI): Not primary etiologic drivers; pathway reference points include Hh morphogens (proteins). Post-translational tubulin modifications (polyglutamylation) modulate ciliary function mechanistically. (getwan2020crisprcas9targetingttc30a pages 16-18) - Cell types (CL): Growth plate chondrocytes; limb bud mesenchymal cells; kidney tubular epithelium; respiratory epithelium; retinal photoreceptors. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Anatomical locations (UBERON): Developing limb/limb bud; thoracic cage/ribs; tracheobronchial tree and lungs; kidney; retina. (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24)
| Gene | Complex / Role | Primary Mechanism | GO Biological Processes (examples) | Cellular Component | Primary Tissues / Cell Types | Representative Phenotypes (HPO) | Sources |
|---|---|---|---|---|---|---|---|
| DYNC2H1 | Dynein-2 heavy chain (retrograde IFT motor) | Retrograde IFT failure; impaired ciliary trafficking | Retrograde ciliary transport; intraflagellar transport; Hedgehog signaling pathway | Primary cilium; axoneme | Growth plate chondrocyte; limb bud mesenchyme; respiratory epithelium | Short ribs [HP:0000773]; Narrow thorax [HP:0000774]; Polydactyly [HP:0010442]; Short long bones [HP:0003026] | (xiong2025anovelcompound pages 8-8, markova2022сlinicalandgenetic pages 9-11) |
| DYNC2LI1 | Dynein-2 light/intermediate chain | Dynein-2 assembly/function defect; impaired retrograde IFT | Retrograde ciliary transport; intraflagellar transport | Dynein complex; primary cilium | Growth plate chondrocyte; limb bud mesenchyme | Narrow thorax [HP:0000774]; Polydactyly [HP:0010442] | (markova2022сlinicalandgenetic pages 9-11) |
| WDR60 | Dynein-2 WD-repeat subunit | Dynein motor assembly/cargo binding defects | Protein complex assembly; retrograde ciliary transport | Dynein complex; cilium | Growth plate chondrocyte; limb bud | Short ribs [HP:0000773]; Polydactyly [HP:0010442] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| WDR34 | Dynein-2 WD-repeat subunit | Dynein assembly / retrograde IFT impairment | Retrograde ciliary transport; intraflagellar transport | Dynein complex; cilium | Growth plate chondrocyte; limb bud | Short long bones [HP:0003026]; Thoracic insufficiency [HP:0004421] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| WDR19 / IFT144 | IFT-A component (WD-repeat) | Disrupted IFT-A cargo retrieval; altered ciliary signaling | Intraflagellar transport; regulation of signaling | IFT-A complex; ciliary base | Kidney tubular epithelium; retinal photoreceptor; growth plate | Renal cysts [HP:0000107]; Retinal degeneration [HP:0000556]; Narrow thorax [HP:0000774] | (markova2022сlinicalandgenetic pages 9-11) |
| IFT140 | IFT-A core subunit | Loss/reduction of cilia; altered SHH signaling | Intraflagellar transport; Hedgehog signaling pathway | Primary cilium; IFT-A complex | Growth plate chondrocyte; retina; kidney | Thoracic dystrophy; Retinal degeneration [HP:0000556]; Renal cysts [HP:0000107] | (francis2023autonomousandnoncell pages 20-24) |
| IFT172 | IFT-B component | IFT-B destabilization; impaired anterograde transport | Intraflagellar transport; cilium assembly | IFT particle B; axoneme | Limb bud mesenchyme; growth plate | Polydactyly [HP:0010442]; Short long bones [HP:0003026] | (getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 7-9) |
| IFT80 | IFT-B core subunit | Impaired anterograde IFT; defective chondrocyte differentiation | Intraflagellar transport; chondrocyte differentiation | IFT complex B; cilium | Growth plate chondrocyte; limb bud | Short long bones [HP:0003026]; Thoracic insufficiency [HP:0004421] | (getwan2020crisprcas9targetingttc30a pages 19-21, getwan2020crisprcas9targetingttc30a pages 16-18) |
| IFT52 | IFT-B core subunit | IFT particle assembly defect; reduced cilia function | Intraflagellar transport; cilium assembly | IFT complex B; axoneme | Limb bud mesenchyme | Polydactyly [HP:0010442]; Short long bones [HP:0003026] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| WDR35 / IFT121 | IFT-A component | Defective cargo retrieval; altered signaling | Retrograde ciliary transport; intraflagellar transport | IFT-A complex; ciliary base | Growth plate; kidney tubule | Narrow thorax [HP:0000774]; Renal cysts [HP:0000107] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| TTC21B / IFT139 | IFT-A (TTC21B) | Retrograde IFT regulation; modulates SHH signaling | Intraflagellar transport; regulation of Hedgehog signaling | IFT-A complex; cilium | Growth plate chondrocyte; kidney | Polydactyly [HP:0010442]; Cystic kidney disease [HP:0000107] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| TRAF3IP1 / IFT54 | IFT-B associated | IFT-B accessory; tubulin/IFT coupling; cilia assembly | Intraflagellar transport; cilium assembly | IFT particle; ciliary axoneme | Limb bud mesenchyme; renal epithelium | Limb anomalies; Renal involvement [HP:0000107] | (getwan2020crisprcas9targetingttc30a pages 7-9, getwan2020crisprcas9targetingttc30a pages 16-18) |
| IFT43 | IFT-A satellite subunit | IFT-A stability / trafficking defects | Intraflagellar transport; cilium organization | IFT-A complex; cilium | Growth plate chondrocyte | SRPS features: Short ribs [HP:0000773]; Polydactyly [HP:0010442] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| IFT22 | IFT-associated small GTPase | IFT regulation; axonemal trafficking | Intraflagellar transport; small GTPase mediated transport | Cilium; IFT particles | Limb bud mesenchyme | Polydactyly [HP:0010442]; Short long bones [HP:0003026] | (getwan2020crisprcas9targetingttc30a pages 16-18) |
| NEK1 | NIMA-related kinase; ciliogenesis regulator | Altered cilium assembly / cell-cycle linked cilia defects | Regulation of cilium assembly; cell cycle regulation | Basal body; centrosome; cilium | Kidney tubular epithelium; growth plate | Renal cysts [HP:0000107]; Skeletal dysplasia features | (getwan2020crisprcas9targetingttc30a pages 16-18) |
Table: Compact table summarizing key genes, their complexes/roles, primary mechanisms, exemplar GO processes, cellular locations, affected tissues/cell types and representative HPO phenotypes for Short-Rib Polydactyly / Short-Rib Thoracic Dysplasia, with supporting source IDs from the gathered evidence.
3) Biological Processes (GO) disrupted - Intraciliary transport; retrograde ciliary transport; cilium assembly/organization; Hedgehog signaling pathway; chondrocyte differentiation; epithelial morphogenesis of branching organs (lung); kidney tubule development. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)
4) Cellular Components - Primary cilium (axoneme, ciliary membrane), basal body/centrosome; IFT-A and IFT-B particle complexes; dynein-2 motor complex. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)
5) Disease Progression (sequence from genotype to phenotype) - Initiating lesion: Biallelic pathogenic variants in dynein-2 (e.g., DYNC2H1) or IFT-A/B genes impair retrograde/anterior IFT and/or ciliogenesis. (xiong2025anovelcompound pages 8-8, francis2023autonomousandnoncell pages 20-24) - Cellular dysfunction: Reduced/abnormal ciliation and defective trafficking in chondrocytes/mesenchyme lead to mis-specified Hh signaling gradients and growth-plate maturation defects. (francis2023autonomousandnoncell pages 16-20, getwan2020crisprcas9targetingttc30a pages 16-18) - Tissue/organ effects: Abnormal endochondral ossification yields short ribs/long bones and narrow bell-shaped thorax; limb patterning errors yield polydactyly. Ciliary dysfunction in kidney tubules predisposes to cystic changes; retinal involvement leads to degeneration in overlapping phenotypes. (francis2023autonomousandnoncell pages 20-24, getwan2020crisprcas9targetingttc30a pages 16-18) - Clinical manifestation: Perinatal respiratory failure due to thoracic insufficiency is a major determinant of lethality; spectrum overlaps with Jeune asphyxiating thoracic dystrophy and Mainzer–Saldino. (markova2022сlinicalandgenetic pages 9-11)
6) Phenotypic Manifestations (HPO) - Core skeletal: Short ribs (HP:0000773), Narrow thorax (HP:0000774), Short long bones (HP:0003026), Polydactyly (HP:0010442), Thoracic insufficiency (HP:0004421). (francis2023autonomousandnoncell pages 16-20, markova2022сlinicalandgenetic pages 9-11) - Multisystem (variable): Renal cysts (HP:0000107), Retinal degeneration (HP:0000556). (francis2023autonomousandnoncell pages 20-24)
7) Nosology and spectrum - Historical SRPS types I–IV are now encompassed by SRTD subtypes with/without polydactyly; there is broad overlap with Jeune asphyxiating thoracic dystrophy and Mainzer–Saldino syndrome, reflecting shared ciliary pathobiology. (markova2022сlinicalandgenetic pages 9-11, francis2023autonomousandnoncell pages 16-20)
8) Recent developments and latest research (2023–2024 priority) - IFT-A defects and cell autonomy: Mouse Ift140 studies (2023) delineate both cell-autonomous (e.g., limb mesenchyme, neural crest) and non–cell-autonomous contributions to structural birth defects, linking cilia loss to altered Shh signaling and thoracic/lung hypoplasia, craniofacial malformations, and polydactyly. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Dynein-2 genetics and diagnostics: Recent clinical genetics highlight recurring DYNC2H1 causal variants and use of prenatal WES/RNA-seq to resolve ambiguous ultrasound phenotypes in SRTD/Jeune families. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Mechanistic breadth in IFT disruption: Experimental systems emphasize that perturbations across IFT-B core (IFT80/IFT172) and IFT-A (TTC21B, WDR35, IFT43) converge on ciliary transport failure and Hh misregulation in skeletal lineages. bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 19-21)
9) Current applications and real-world implementations - Prenatal imaging plus genomics: Systematic second/third-trimester ultrasound recognizing short ribs, narrow thorax, and limb anomalies combined with exome sequencing is increasingly used to confirm SRPS/SRTD and counsel families. Recent dynein-2 case series and reports underscore WES utility in recurrent-affected families and variant interpretation. Hereditas, Jan 2025, https://doi.org/10.1186/s41065-025-00375-x (xiong2025anovelcompound pages 8-8) - Model systems for functional interpretation: IFT/dynein-2 perturbation in Xenopus and mouse models reproduces cardinal human phenotypes (polydactyly, thoracic dystrophy, renal cysts), supporting variant pathogenicity assessment frameworks. bioRxiv, Nov 2020, https://doi.org/10.1101/2020.11.27.400994; bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24)
10) Expert opinions and analysis - SRTD as a ciliopathy spectrum: Reviews and compiled clinical genetics emphasize DYNC2H1 as a predominant gene in SRTD3 and underscore that respiratory failure from thoracic insufficiency drives lethality; exome sequencing is the primary tool to resolve genetic heterogeneity. (markova2022сlinicalandgenetic pages 9-11) - Quote: “Pathogenic variants of DYNC2H1… have been reported to cause SRTD3,” and phenotypes include “a narrow thorax, short ribs, shortened tubular bones.” BMC Med Genomics abstract (supportive of dynein-2 causality; see also compiled overview) (markova2022сlinicalandgenetic pages 9-11) - Developmental windows and lineage specificity: Ift140 studies indicate early embryonic windows and lineage-specific disruptions (neural crest, limb mesenchyme) underlie polydactyly/thoracic and craniofacial defects, clarifying variable phenotypic expressivity within the SRTD spectrum. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 16-20)
11) Relevant statistics and data - Gene burden: DYNC2H1 is frequently implicated in SRTD/SRPS; curated overviews report it as the leading cause of SRTD3 and a substantial fraction of SRTD overall. (markova2022сlinicalandgenetic pages 9-11) - Multisystem frequencies: IFT140-related SRTD often associates with retinal and renal involvement, consistent with IFT-A roles and mouse knockouts demonstrating renal and ciliary defects. bioRxiv, Jun 2023, https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 20-24)
Ontology-annotated annotations for knowledge base - Gene/Protein annotations (HGNC): DYNC2H1; DYNC2LI1; WDR60; WDR34; IFT140; WDR19 (IFT144); WDR35 (IFT121); TTC21B (IFT139); IFT172; IFT80; IFT52; TRAF3IP1 (IFT54); IFT43; IFT22; NEK1. (getwan2020crisprcas9targetingttc30a pages 16-18, markova2022сlinicalandgenetic pages 9-11, xiong2025anovelcompound pages 8-8) - GO Processes: Intraciliary/Intraflagellar transport; Retrograde ciliary transport; Cilium assembly; Hedgehog signaling pathway; Chondrocyte differentiation; Kidney tubule development. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Cellular Components: Primary cilium; Ciliary axoneme; Basal body/centrosome; IFT-A/B complexes; Dynein-2 complex. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Cell types (CL): Growth plate chondrocyte; Limb bud mesenchymal cell; Renal tubular epithelial cell; Respiratory epithelial cell; Retinal photoreceptor cell. (getwan2020crisprcas9targetingttc30a pages 16-18, francis2023autonomousandnoncell pages 20-24) - Anatomy (UBERON): Limb bud; Rib/thoracic cage; Lung; Kidney; Retina. (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Phenotypes (HPO): Short ribs (HP:0000773); Narrow thorax (HP:0000774); Short long bones (HP:0003026); Polydactyly (HP:0010442); Thoracic insufficiency (HP:0004421); Renal cysts (HP:0000107); Retinal degeneration (HP:0000556). (francis2023autonomousandnoncell pages 16-20, francis2023autonomousandnoncell pages 20-24) - Chemical entities (CHEBI): Not primary; note role of tubulin post-translational modifications in ciliary function (polyglutamylation). (getwan2020crisprcas9targetingttc30a pages 16-18)
Evidence items (with URLs and dates) - Francis et al. “Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects.” bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132 (francis2023autonomousandnoncell pages 20-24, francis2023autonomousandnoncell pages 16-20) - Getwan et al. “CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease.” bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994 (getwan2020crisprcas9targetingttc30a pages 16-18, getwan2020crisprcas9targetingttc30a pages 18-19, getwan2020crisprcas9targetingttc30a pages 7-9, getwan2020crisprcas9targetingttc30a pages 19-21) - Xiong et al. “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 (xiong2025anovelcompound pages 8-8) - Markova et al. “Clinical and genetic characteristics of skeletal ciliopathies—short-rib thoracic dysplasia.” 2022. Summary source for DYNC2H1 predominance and clinical spectrum. (markova2022сlinicalandgenetic pages 9-11)
Limitations and notes - Several mechanistic sources are preprints (2020–2023 bioRxiv) but represent authoritative groups and align with established ciliopathy biology; peer-reviewed 2023–2024 SRPS-specific systematic reviews were not captured in the present evidence set. - For comprehensive MONDO/OMIM mapping and a complete gene list, cross-reference community databases during curation.
References
(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.
(francis2023autonomousandnoncell pages 16-20): Richard Francis, Jovenal T San Agustin, Heather L. Szabo Rogers, Cheng Cui, Julie A. Jonassen, Thibaut Eguether, John A. Follit, Cecilia W. Lo, and Gregory J. Pazour. Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132, doi:10.1101/2023.06.07.544132. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 16-18): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(markova2022сlinicalandgenetic pages 9-11): TV Markova, VM Kenis, and EV Melchenko. Сlinical and genetic characteristics of skeletal cyliopathies–short-rib thoracic dysplasia. Unknown journal, 2022.
(francis2023autonomousandnoncell pages 20-24): Richard Francis, Jovenal T San Agustin, Heather L. Szabo Rogers, Cheng Cui, Julie A. Jonassen, Thibaut Eguether, John A. Follit, Cecilia W. Lo, and Gregory J. Pazour. Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.07.544132, doi:10.1101/2023.06.07.544132. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 7-9): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 19-21): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.
(getwan2020crisprcas9targetingttc30a pages 18-19): Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, and Soeren S. Lienkamp. Crispr/cas9 targeting ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease. bioRxiv, Nov 2020. URL: https://doi.org/10.1101/2020.11.27.400994, doi:10.1101/2020.11.27.400994. This article has 0 citations and is from a poor quality or predatory journal.