Ellis-van Creveld syndrome (EvC) is an autosomal recessive skeletal ciliopathy caused by mutations in EVC or EVC2 genes, which encode proteins essential for Hedgehog signaling at the primary cilium. It is characterized by disproportionate short-limb short stature, postaxial polydactyly, ectodermal dysplasia (including nail and dental anomalies), and congenital heart defects (most commonly a common atrium or single atrium). The syndrome has a notably high prevalence in the Old Order Amish population due to a founder effect.
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name: Ellis-van Creveld Syndrome
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
description: >
Ellis-van Creveld syndrome (EvC) is an autosomal recessive skeletal ciliopathy
caused by mutations in EVC or EVC2 genes, which encode proteins essential for
Hedgehog signaling at the primary cilium. It is characterized by disproportionate
short-limb short stature, postaxial polydactyly, ectodermal dysplasia (including
nail and dental anomalies), and congenital heart defects (most commonly a common
atrium or single atrium). The syndrome has a notably high prevalence in the Old
Order Amish population due to a founder effect.
disease_term:
preferred_term: Ellis-van Creveld syndrome
term:
id: MONDO:0009162
label: Ellis-van Creveld syndrome
parents:
- Ciliopathies
- Short-Rib Dysplasias
inheritance:
- name: Autosomal Recessive
description: >
Autosomal recessive inheritance. High prevalence in the Old Order Amish
community due to a founder mutation.
evidence:
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive
skeletal dysplasia characterized by short limbs, short ribs, postaxial
polydactyly and dysplastic nails and teeth.
explanation: >-
Landmark paper confirming autosomal recessive inheritance of EvC.
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
The disease was mapped to chromosome 4p16 in nine Amish subpedigrees
and single pedigrees from Mexico, Ecuador and Brazil.
explanation: >-
EvC was mapped through Amish pedigrees, reflecting the founder
effect in this population.
prevalence:
- population: Global reported literature
percentage: approximately 150 reported cases worldwide
notes: >-
Review literature describes Ellis-van Creveld syndrome as very rare
globally, with about 150 reported cases and no precise worldwide prevalence
estimate.
evidence:
- reference: PMID:17547743
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia
characterized by short ribs, polydactyly, growth retardation, and
ectodermal and heart defects. It is a rare disease with approximately 150
cases reported worldwide.
explanation: >-
This Orphanet review provides the clearest PubMed-abstract estimate of
total reported EvC cases worldwide.
- population: Old Order Amish live births
percentage: 1 in 5,000 live births
notes: >-
Founder-enriched Amish prevalence is dramatically higher than the reported
non-Amish birth prevalence of about 7 per 1,000,000.
evidence:
- reference: PMID:22232726
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ellis-van Creveld syndrome is a rare congenital genetic disorder having
autosomal recessive inheritance. It is a syndrome affecting the Amish
population of Pennsylvania in USA with prevalence rate of 1/5,000 live at
birth. In non-Amish population, the birth prevalence is 7/1,000,000.
explanation: >-
This case review abstract gives concrete founder-population and non-Amish
birth prevalence estimates for EvC.
pathophysiology:
- name: Hedgehog Signaling Disruption
description: >
EVC and EVC2 form a complex at the base of the primary cilium that is
required for transduction of Hedgehog (Hh) signaling. The complex interacts
with Smoothened (Smo) and regulates Gli transcription factor processing.
Loss of function of either protein impairs Hh-dependent processes including
skeletal patterning, endochondral ossification, and cardiac septation.
cell_types:
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: Hedgehog Signaling
term:
id: GO:0007224
label: smoothened signaling pathway
- preferred_term: Endochondral Ossification
term:
id: GO:0001958
label: endochondral ossification
- preferred_term: Limb Development
term:
id: GO:0060173
label: limb development
evidence:
- reference: PMID:23026747
reference_title: "The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia."
supports: SUPPORT
snippet: >-
Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone
development.
explanation: >-
Demonstrates that EVC/EVC2 mutations specifically disrupt Hedgehog
signaling in skeletal and dental tissues.
- reference: PMID:23026747
reference_title: "The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia."
supports: SUPPORT
snippet: >-
Evc and Evc2 are mutually required for localizing to primary cilia
and also for maintaining their normal protein levels.
explanation: >-
Shows the EVC/EVC2 complex is interdependent for ciliary
localization and protein stability.
evidence_source: MODEL_ORGANISM
- reference: PMID:23026747
reference_title: "The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia."
supports: SUPPORT
snippet: >-
we found Smo to co-precipitate with Evc/Evc2, indicating that
in some cells Hh signaling requires direct interaction of Smo
with the Evc/Evc2 complex.
explanation: >-
Demonstrates direct physical interaction between Smo and the
Evc/Evc2 complex in Hedgehog signal transduction.
evidence_source: MODEL_ORGANISM
- name: Primary Cilium Dysfunction
description: >
The EVC/EVC2 complex localizes to a signaling microdomain at the base
of primary cilia, tethered by EFCAB7 and IQCE. Disruption impairs the
processing of GLI transcription factors, particularly GLI2 activation,
which mediates Hedgehog pathway responses in growth plate chondrocytes
and cardiac progenitors.
biological_processes:
- 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:24582806
reference_title: "EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia."
supports: SUPPORT
snippet: >-
The EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling
microdomain at the base of cilia.
explanation: >-
Identifies the molecular mechanism by which EVC-EVC2 is anchored
at the ciliary base for Hedgehog signal transduction.
evidence_source: IN_VITRO
- reference: PMID:24582806
reference_title: "EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia."
supports: SUPPORT
snippet: >-
EFCAB7 depletion mimics the Weyers cellular phenotype-the
mislocalization of EVC-EVC2 within cilia and impaired activation
of the transcription factor GLI2.
explanation: >-
Shows that mislocalization of EVC-EVC2 within cilia impairs
GLI2 activation, linking ciliary dysfunction to disease phenotype.
evidence_source: IN_VITRO
- reference: PMID:23026747
reference_title: "The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia."
supports: SUPPORT
snippet: >-
Gli3 recruitment to cilia tips was reduced and Sufu/Gli3
dissociation was impaired.
explanation: >-
In Evc2-deficient chondrocytes, Gli3 processing at cilia tips
is impaired, demonstrating the ciliary signaling defect.
evidence_source: MODEL_ORGANISM
- name: Cardiac Septation Defect
description: >
Hedgehog signaling is required for proper atrioventricular septation.
Disruption of EVC/EVC2-mediated Hh signaling leads to common atrium
and other cardiac septal defects through impaired endocardial cushion
development. The cardiac phenotype is strongly reminiscent of
heterotaxy syndromes, suggesting a cilia-dependent mechanism.
biological_processes:
- preferred_term: Heart Development
term:
id: GO:0007507
label: heart development
- preferred_term: Cardiac Septum Morphogenesis
term:
id: GO:0060411
label: cardiac septum morphogenesis
evidence:
- reference: PMID:21533779
reference_title: "Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases."
supports: PARTIAL
snippet: >-
Twenty-eight (88%) had an endocardial cushion defect, with 15 of
these having primary failure of atrial septation resulting in CA.
explanation: >-
In 32 EvC patients with CHD, 88% had endocardial cushion defects,
with common atrium being the most characteristic cardiac lesion.
- reference: PMID:21533779
reference_title: "Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases."
supports: SUPPORT
snippet: >-
The frequent association of these abnormalities is strongly
reminiscent of the cardiac phenotype found in patients with
heterotaxy syndromes.
explanation: >-
Cardiac phenotype in EvC resembles heterotaxy, suggesting
shared cilia-dependent cardiac morphogenesis mechanism.
- reference: PMID:21533779
reference_title: "Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases."
supports: SUPPORT
snippet: >-
EVC and EVC2 proteins may be important for cilia function, which
is implicated in the pathogenesis of heterotaxy syndromes.
explanation: >-
Suggests a cilia-related mechanism, but the statement is speculative and only partially supports the mechanistic claim.
phenotypes:
- name: Disproportionate Short Stature
description: >
Short-limb disproportionate short stature. Adult height typically
ranges from 109 to 155 cm.
phenotype_term:
preferred_term: Disproportionate short-limb short stature
term:
id: HP:0008873
label: Disproportionate short-limb short stature
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal
dysplasia characterized by short ribs, polydactyly, growth
retardation, and ectodermal and heart defects.
explanation: >-
Comprehensive review identifies growth retardation as a
cardinal feature of EvC.
- name: Postaxial Polydactyly
description: >
Postaxial (ulnar/fibular) polydactyly of hands, present in nearly all
affected individuals. A cardinal feature of the syndrome.
phenotype_term:
preferred_term: Postaxial hand polydactyly
term:
id: HP:0001162
label: Postaxial hand polydactyly
evidence:
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
an autosomal recessive skeletal dysplasia characterized by short
limbs, short ribs, postaxial polydactyly and dysplastic nails
and teeth.
explanation: >-
Postaxial polydactyly is a defining feature of EvC syndrome.
- name: Short Ribs and Narrow Chest
description: >
Short ribs with a narrow thorax that may cause respiratory compromise
in the neonatal period.
phenotype_term:
preferred_term: Narrow chest
term:
id: HP:0000774
label: Narrow chest
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Prognosis is linked to the respiratory difficulties in the first
months of life due to thoracic narrowness and possible heart defects.
explanation: >-
Thoracic narrowness from short ribs is a major prognostic
factor, causing respiratory difficulties in neonates.
- name: Congenital Heart Defect
description: >
Congenital heart defects occur in approximately 60% of individuals,
most commonly common atrium (single atrium) and endocardial cushion
defects. Persistent left superior vena cava and pulmonary venous
abnormalities are also reported.
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
evidence:
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
Congenital cardiac defects, most commonly a defect of primary
atrial septation producing a common atrium, occur in 60% of
affected individuals.
explanation: >-
Landmark paper establishing 60% frequency of cardiac defects,
with common atrium as the most characteristic lesion.
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Heart defects, especially abnormalities of atrial septation,
occur in about 60% of cases.
explanation: >-
Comprehensive review confirms 60% cardiac defect frequency.
- reference: PMID:21533779
reference_title: "Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases."
supports: SUPPORT
snippet: >-
Persistent left superior vena cava (LSVC) and pulmonary venous
connection abnormalities were common. The incidence of persistent
LSVC and pulmonary venous abnormalities were greater than
previously reported for patients with EVC.
explanation: >-
Large cardiac case series reveals venous connection abnormalities
are more common in EvC than previously recognized.
- name: Nail Dysplasia
description: >
Hypoplastic or dysplastic nails, a component of the ectodermal
dysplasia features.
phenotype_term:
preferred_term: Nail dysplasia
term:
id: HP:0002164
label: Nail dysplasia
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
cardinal features are short stature, short ribs, polydactyly,
and dysplastic fingernails and teeth.
explanation: >-
Dysplastic fingernails are a cardinal feature of EvC.
- name: Dental Anomalies
description: >
Dental anomalies including neonatal teeth, absent or small teeth,
abnormal tooth shape, and delayed eruption. Part of the ectodermal
dysplasia spectrum.
phenotype_term:
preferred_term: Abnormality of the dentition
term:
id: HP:0000164
label: Abnormality of the dentition
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
cardinal features are short stature, short ribs, polydactyly,
and dysplastic fingernails and teeth.
explanation: >-
Dysplastic teeth are a cardinal feature of EvC.
- name: Short Upper Lip with Multiple Frenula
description: >
Short upper lip bound by multiple frenula (mucosal folds) is a
characteristic facial feature.
phenotype_term:
preferred_term: Narrow mouth
term:
id: HP:0000160
label: Narrow mouth
- name: Genu Valgum
description: >
Knock knees (genu valgum) is common and may be progressive.
phenotype_term:
preferred_term: Genu valgum
term:
id: HP:0002857
label: Genu valgum
genetic:
- name: EVC Mutations
association: Causative
notes: >
Homozygous or compound heterozygous mutations in EVC on chromosome
4p16. The EVC protein localizes to the base of the primary cilium
and is required for Hedgehog signal transduction. Mutations account
for approximately 31% of EvC cases.
evidence:
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
We have identified a new gene (EVC), encoding a 992-amino-acid
protein, that is mutated in individuals with EvC.
explanation: >-
Landmark paper identifying EVC as a causative gene for EvC
syndrome.
- reference: PMID:10700184
reference_title: "Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis."
supports: SUPPORT
snippet: >-
We identified a splice-donor change in an Amish pedigree and
six truncating mutations and a single amino acid deletion in
seven pedigrees.
explanation: >-
Describes the mutation spectrum in EVC including truncating
and splice-site mutations.
- name: EVC2 Mutations
association: Causative
notes: >
Homozygous or compound heterozygous mutations in EVC2 (also on 4p16,
in a head-to-head configuration with EVC). EVC2 forms an obligate
complex with EVC at the cilium. Patients with EVC2 mutations are
phenotypically indistinguishable from those with EVC mutations.
evidence:
- reference: PMID:12571802
reference_title: "Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
We now report that mutations in EVC2 also cause EvC. These two
genes lie in a head-to-head configuration that is conserved from
fish to man.
explanation: >-
Identifies EVC2 as a second causative gene in a head-to-head
configuration with EVC.
- reference: PMID:12571802
reference_title: "Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Affected individuals with mutations in EVC and EVC2 have the
typical spectrum of features and are phenotypically
indistinguishable.
explanation: >-
Confirms that EVC and EVC2 mutations produce identical
clinical phenotypes.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
description: >-
Ellis-van Creveld syndrome is diagnosed from characteristic clinical and
radiographic findings (disproportionate short stature, postaxial
polydactyly, chondrodysplasia, and the EvC-zone dental/oral findings) and
confirmed by molecular genetic testing of the EVC/EVC2 ciliary Hedgehog
genes and other short-rib/ciliopathy loci. Early echocardiography is a
diagnostic priority because of the high frequency of common atrium /
atrioventricular canal defects.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:37903214
reference_title: "Ellis-van Creveld Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of EVC syndrome is established in a proband with characteristic clinical and radiographic findings and biallelic pathogenic variants in DYNC2H1, DYNC2LI1, EVC, EVC2, GLI, SMO, or WDR35 or a heterozygous pathogenic variant in PRKACA or PRKACB identified by molecular genetic testing."
explanation: >-
GeneReviews defines the combined clinical/radiographic and molecular
diagnostic criteria for EvC syndrome across its ciliary Hedgehog genes.
treatments:
- name: Cardiac Surgery
description: >
Surgical repair of congenital heart defects, particularly common
atrium repair and ASD closure.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
located_in:
preferred_term: heart
term:
id: UBERON:0000948
label: heart
evidence:
- reference: PMID:21533779
reference_title: "Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases."
supports: NO_EVIDENCE
snippet: >-
Thirty-two pediatric patients with congenital heart disease (CHD)
and EVC syndrome were identified in the PCCC database.
explanation: >-
Snippet identifies EvC patients with CHD but does not provide direct evidence for cardiac surgery outcomes or use.
- name: Orthopedic Management
description: >
Management of polydactyly (surgical removal of extra digits),
genu valgum correction, and other skeletal manifestations.
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Orthopedic follow-up is required to manage the bones deformities.
explanation: >-
Comprehensive review recommends orthopedic follow-up for
skeletal deformities in EvC.
- name: Dental Management
description: >
Comprehensive dental care for anomalous dentition including
prosthetic replacements and orthodontic intervention.
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Professional dental care should be considered for management
of the oral manifestations.
explanation: >-
Review recommends professional dental care for oral
manifestations of EvC.
- name: Respiratory Support
description: >
Management of respiratory distress in the neonatal period due to
narrow chest and short ribs.
evidence:
- reference: PMID:17547743
reference_title: "Ellis-van Creveld syndrome."
supports: SUPPORT
snippet: >-
Management during the neonatal period is mostly symptomatic,
involving treatment of the respiratory distress due to narrow
chest and heart failure.
explanation: >-
Neonatal respiratory support is a key early management priority.
datasets: []
references:
- reference: PMID:37903214
title: "Ellis-van Creveld Syndrome."
tags:
- GeneReviews
findings: []
Pathophysiology description Ellis-van Creveld syndrome is a skeletal ciliopathy driven by defective Hedgehog (Hh) signal transduction at the primary cilium due to loss of function in the EVC–EVC2 transmembrane complex or disruption of its ciliary recruitment by intraflagellar transport components. The EVC–EVC2 heterodimer localizes to a specialized ciliary subdomain termed the EvC zone, where it forms a signaling complex with Smoothened (SMO) to promote dissociation of SUFU from GLI proteins and enable GLI trafficking and activation. Chondrocytes in the growth plate depend on these events for Indian hedgehog (IHH)-dependent proliferation and endochondral ossification; when impaired, proliferative and hypertrophic zones are reduced, explaining disproportionate short stature, short ribs, and polydactyly. Cardiac malformations, especially atrioventricular canal (AVC) defects and common atrium, arise from disrupted Sonic hedgehog (SHH) signaling during endocardial cushion and septal development; some evidence links this axis to laterality/heterotaxy pathways. Mechanistic variants in IFT-A (e.g., WDR35/IFT121) phenocopy EvC by preventing ciliary recruitment of EVC/EVC2 and SMO, collapsing downstream Hh readouts. Together, these data define EvC as a cilia-localized failure of Hh transduction with tissue-specific consequences in cartilage, heart, and ectodermal derivatives (teeth, nails) (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9, caparrosmartin2015specificvariantsin pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
1) Core Pathophysiology - Primary mechanism: loss of EVC–EVC2 complex function at the EvC zone of the primary cilium attenuates Hh signaling downstream of SMO by impairing SUFU–GLI dissociation and GLI trafficking/activation. In chondrocytes, this reduces IHH target expression and endochondral ossification. EvC is therefore a cilia-localized signal transduction defect impacting skeletal and cardiac morphogenesis (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9). - Molecular pathways dysregulated: canonical Hedgehog signaling (SHH/IHH→PTCH1→SMO→GLI). EVC/EVC2 physically associate with SMO in cilia; EVC/EVC2 loss reduces Hh output even when SUFU is absent, indicating roles at GLI activation/trafficking in the cilium (caparrosmartin2013theciliaryevcevc2 pages 7-9). - Cellular processes affected: ciliary trafficking of SMO/GLI, SUFU–GLI complex dynamics, growth plate chondrocyte proliferation and hypertrophic differentiation, endochondral ossification; cardiac septation via SHH signaling in endocardial cushions (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Key mechanistic quotes - “A Smoothened‑Evc2 complex transduces the Hedgehog signal at primary cilia.” (Dorn et al. 2012) (caparrosmartin2013theciliaryevcevc2 pages 7-9). - “The ciliary Evc/Evc2 complex… controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.” (Caparrós‑Martín et al. 2013) (caparrosmartin2013theciliaryevcevc2 pages 1-2). - “Monoubiquitination of EVC‑EVC2 cytosolic tails greatly reduces their protein levels… modification with the small ubiquitin‑related modifier SUMO3… enhances complex accumulation at the EvC zone.” (Barbeito et al. 2023) (barbeito2023evcevc2complexstability pages 2-4). - “Specific variants in WDR35 cause a distinctive form of Ellis‑van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium.” (Caparrós‑Martín et al. 2015) (caparrosmartin2015specificvariantsin pages 1-2).
2) Key Molecular Players - Genes/Proteins (HGNC): - EVC (HGNC:3500) and EVC2 (HGNC:23301): transmembrane heterodimer at the EvC zone; required for Hh transduction downstream of SMO; EVC2 C‑terminal W‑peptide (including FV motif) mediates EvC‑zone targeting and stabilizes the complex (caparrosmartin2013theciliaryevcevc2 pages 1-2, barbeito2023evcevc2complexstability pages 2-4, louie2020molecularandcellular pages 3-5). - SMO (HGNC:11119): ciliary effector that binds EVC/EVC2 at EvC zone to propagate Hh signaling to GLI; SMO ciliary entry can occur without EVC/EVC2, but productive signaling is reduced (caparrosmartin2013theciliaryevcevc2 pages 7-9). - GLI3 (HGNC:4311) and SUFU (HGNC:20469): EVC/EVC2 promote SUFU–GLI dissociation and GLI trafficking to the ciliary tip to generate activator forms; loss redistributes GLI3 and enriches GLI3 repressor (caparrosmartin2013theciliaryevcevc2 pages 1-2). - EFCAB7 (HGNC:26058) and IQCE (HGNC:29063): tether the EVC/EVC2 complex to EvC zone; SUMO3 enhances tethering, ubiquitination reduces protein levels (barbeito2023evcevc2complexstability pages 2-4). - WDR35/IFT121 (HGNC:15866): IFT-A component required for entry/recruitment of EVC/EVC2 and SMO into cilia; disease variants prevent ciliary localization and collapse Hh readouts (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5).
Chemical entities: SAG (SMO agonist) used in functional studies to probe Hh responsiveness; proteasome inhibitor MG132 stabilizes hypomorphic WDR35Δ3 in vitro (experimental tools) (caparrosmartin2015specificvariantsin pages 4-5).
Cell types (CL): growth plate chondrocytes (CL:0000138) are primary effectors of IHH signaling in bone; endocardial cushion mesenchyme (CL:0002519) in cardiac septation (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Anatomical locations (UBERON): primary cilium/EvC zone near the transition zone (GO/UBERON mapping); growth plate of bone (UBERON:0003860); atrioventricular canal (UBERON:0002084); cardiac septum (UBERON:0002080); tooth (UBERON:0001091) (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
3) Biological Processes (GO terms; disrupted in EvC) - Hedgehog signaling pathway (GO:0007224): attenuated due to defective EVC–EVC2-SMO complex function and impaired SUFU–GLI dynamics (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9). - Chondrocyte differentiation (GO:0030154) and endochondral ossification (GO:0001958): reduced proliferative/hypertrophic zones and target gene expression in Evc/Evc2‑deficient growth plates (caparrosmartin2013theciliaryevcevc2 pages 1-2). - Intraflagellar transport (GO:0035725): impaired recruitment of EVC/EVC2 and SMO to cilia in WDR35/IFT121 mutants (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5). - Protein ubiquitination (GO:0016567) and protein SUMOylation (GO:0016925): post-translational modifications modulate EVC–EVC2 stability and EvC‑zone targeting (barbeito2023evcevc2complexstability pages 2-4).
4) Cellular Components (GO terms) - Primary cilium (GO:0005929), EvC zone at the ciliary base immediately distal to the transition zone (ciliary transition zone, GO:0035869): site of EVC–EVC2–SMO complex assembly and GLI regulation (caparrosmartin2013theciliaryevcevc2 pages 7-9, barbeito2023evcevc2complexstability pages 2-4). - Ciliary tip: site of GLI accumulation and processing; ciliary base: site of SUFU–GLI dissociation (caparrosmartin2013theciliaryevcevc2 pages 1-2).
5) Disease Progression (sequence of events) - Genetic trigger: biallelic pathogenic variants in EVC or EVC2 (or hypomorphic alleles), or select IFT-A components (e.g., WDR35) (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - Ciliary defect: failure of EVC–EVC2 complex to accumulate at EvC zone, or inability of EVC/EVC2 and SMO to enter/recruit to cilia; altered tethering (EFCAB7–IQCE) and post-translational regulation (ubiquitin/SUMO) further reduce complex abundance (caparrosmartin2013theciliaryevcevc2 pages 7-9, barbeito2023evcevc2complexstability pages 2-4, caparrosmartin2015specificvariantsin pages 1-2). - Signaling failure: diminished SUFU–GLI dissociation and GLI trafficking; reduced GLI activator formation and Hh target gene transcription (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9). - Tissue outcomes: in growth plates, decreased IHH signaling reduces proliferative and hypertrophic chondrocyte zones and delays endochondral ossification; in heart, disturbed SHH contributes to AV canal/common atrium defects via impaired endocardial cushion morphogenesis; ectodermal derivatives (teeth/nails) show dysplasia (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
6) Phenotypic Manifestations (HP terms; mechanistic links) - Postaxial polydactyly (HP:0001162), short long bones (HP:0003026), short ribs (HP:0000773): arise from impaired IHH‑dependent growth plate proliferation/differentiation (caparrosmartin2013theciliaryevcevc2 pages 1-2). - Common atrium (HP:0006697), atrioventricular canal defect (HP:0001671): linked to perturbed SHH signaling in cardiac septation; EVC/EVC2/SMO ciliary entry and SHH are emphasized as unifying mechanisms across syndromic AV canal defects (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - Dental/nail anomalies (HP:0000692): reflect ectodermal consequences of ciliary Hh signaling defects (louie2020molecularandcellular pages 3-5, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Recent developments and latest research (2023–2024 priority) - Post-translational control of the EVC–EVC2 complex (2023): endogenous interactome revealed USP7 and confirmed EFCAB7–IQCE; “monoubiquitination… greatly reduces [EVC–EVC2] protein levels,” whereas “modification… with… SUMO3… enhances complex accumulation at the EvC zone,” mapping second EFCAB7-binding motif in EVC2’s W‑peptide (Frontiers in Cell and Developmental Biology, Jul 2023; doi:10.3389/fcell.2023.1190258) (barbeito2023evcevc2complexstability pages 2-4, barbeito2023evcevc2complexstability pages 1-2). - Genotype–phenotype refinement (2020 but clinically impactful): hypomorphic EVC alleles can yield a mild EvC subtype dominated by common atrium/AV canal defect with postaxial polydactyly; patient fibroblasts show reduced EVC/EVC2 levels and fewer EVC2‑positive cilia (Human Mutation, Oct 2020; doi:10.1002/humu.24112) (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Current applications and real-world implementations - Molecular diagnosis: sequencing of EVC/EVC2 plus IFT genes (e.g., WDR35) in EvC phenotypes with ciliary Hh defects; recognition that WDR35 variants can “disrupt the recruitment of the EvC complex and SMO into the cilium,” phenocopying EvC (Human Molecular Genetics, Apr 2015; doi:10.1093/hmg/ddv152) (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5). - Functional readouts: ciliary localization assays for EVC/EVC2/SMO; Hh pathway induction with SMO agonists (e.g., SAG) and GLI1/GLI‑reporters in patient-derived cells; proteasome inhibition (MG132) can stabilize hypomorphic WDR35Δ3 in vitro for mechanistic confirmation (caparrosmartin2015specificvariantsin pages 4-5). - Cardiac risk stratification: expert reviews emphasize SHH’s “unifying role” in AV canal defects across syndromes and the importance of ciliary entry of EVC, EVC2 and SMO (2019–2021), supporting early echocardiographic surveillance in EvC (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Expert opinions and analysis from authoritative sources - Developmental cell biology and human genetics papers converge that the EvC zone functions as a signal relay platform for SMO–EVC/EVC2 to license GLI activation in the cilium; loss produces partial Hh blunting rather than absolute null signaling in many contexts, consistent with viable but severely dysplastic phenotypes (caparrosmartin2013theciliaryevcevc2 pages 7-9, caparrosmartin2013theciliaryevcevc2 pages 1-2, louie2020molecularandcellular pages 3-5). - Cardiac genetics reviews highlight SHH as a shared pathway for AV canal/common atrium in EvC, and suggest that defects in ciliary entry/retention of EVC/EVC2/SMO are pathogenic in the heart as in cartilage (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Relevant statistics and recent data - Estimated EvC incidence ~1 in 60,000 (review synthesis) (Oct 2020; Journal of Developmental Biology; doi:10.3390/jdb8040025) (louie2020molecularandcellular pages 3-5). - Growth plate pathology in Evc/Evc2 mouse models: reduced proliferative and hypertrophic zones with decreased IHH target expression, correlating with limb and rib shortening (Human Molecular Genetics, Oct 2013; doi:10.1093/hmg/dds409) (caparrosmartin2013theciliaryevcevc2 pages 1-2).
Evidence items with PMIDs/DOIs, URLs, and dates - Caparrós‑Martín et al., Human Molecular Genetics, “The ciliary Evc/Evc2 complex…,” Oct 2013. doi:10.1093/hmg/dds409; URL: https://doi.org/10.1093/hmg/dds409 (caparrosmartin2013theciliaryevcevc2 pages 1-2). - Dorn et al., Developmental Cell, “A Smoothened‑Evc2 complex…,” Oct 2012. doi:10.1016/j.devcel.2012.07.004; URL: https://doi.org/10.1016/j.devcel.2012.07.004 (caparrosmartin2013theciliaryevcevc2 pages 7-9). - Barbeito et al., Frontiers in Cell and Developmental Biology, “EVC‑EVC2 complex stability… ubiquitin and SUMO,” Jul 2023. doi:10.3389/fcell.2023.1190258; URL: https://doi.org/10.3389/fcell.2023.1190258 (barbeito2023evcevc2complexstability pages 2-4, barbeito2023evcevc2complexstability pages 1-2). - Caparrós‑Martín et al., Human Molecular Genetics, “Specific variants in WDR35…,” Apr 2015. doi:10.1093/hmg/ddv152; URL: https://doi.org/10.1093/hmg/ddv152 (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5). - Piceci‑Sparascio et al., Human Mutation, “Common atrium/AV canal defect… mild EvC,” Oct 2020. doi:10.1002/humu.24112; URL: https://doi.org/10.1002/humu.24112 (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - Calcagni et al., Genes, “Cardiac Defects and Genetic Syndromes…,” Jul 2021. doi:10.3390/genes12071047; URL: https://doi.org/10.3390/genes12071047 (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - Digilio et al., Clinical Genetics, “Atrioventricular canal defect… unifying role of SHH,” Feb 2019. doi:10.1111/cge.13375; URL: https://doi.org/10.1111/cge.13375 (piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - Louie et al., Journal of Developmental Biology, “Molecular and Cellular Pathogenesis of EvC…,” Oct 2020. doi:10.3390/jdb8040025; URL: https://doi.org/10.3390/jdb8040025 (louie2020molecularandcellular pages 3-5).
Gene/protein annotations with ontology terms - EVC (HGNC:3500): GO processes—Hedgehog signaling (GO:0007224); Cellular component—primary cilium/EvC zone (GO:0005929/GO:0035869); Phenotypes—HP:0001162, HP:0000773, HP:0001671 (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20). - EVC2 (HGNC:23301): GO processes—Hedgehog signaling; protein ubiquitination (GO:0016567); protein SUMOylation (GO:0016925); Cellular component—EvC zone; Phenotypes—polydactyly, dental anomalies (barbeito2023evcevc2complexstability pages 2-4, louie2020molecularandcellular pages 3-5). - SMO (HGNC:11119): GO—Hedgehog signaling; Cellular component—ciliary membrane/EvC zone; Phenotypes—cardiac septation defects (caparrosmartin2013theciliaryevcevc2 pages 7-9, caparrosmartin2015specificvariantsin pages 1-2). - GLI3 (HGNC:4311)/SUFU (HGNC:20469): GO—GLI-mediated transcription; proteolytic processing; Cellular component—ciliary tip/base; Phenotypes—skeletal anomalies (caparrosmartin2013theciliaryevcevc2 pages 1-2). - EFCAB7 (HGNC:26058)/IQCE (HGNC:29063): GO—ciliary targeting; protein SUMOylation/ubiquitination; Cellular component—EvC zone tether; Phenotypes—EvC spectrum when disrupted (barbeito2023evcevc2complexstability pages 2-4). - WDR35/IFT121 (HGNC:15866): GO—intraciliary transport (IFT‑A); Cellular component—ciliary shaft/base; Phenotypes—EvC‑like skeletal/cardiac features (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5).
Phenotype associations (HP terms) - HP:0001162 Postaxial polydactyly; HP:0000773 Short ribs; HP:0003026 Short long bones; HP:0006697 Common atrium; HP:0001671 Atrioventricular canal defect; HP:0000692 Abnormal dentition (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20, louie2020molecularandcellular pages 3-5).
Cell type involvement (CL terms) - CL:0000138 Growth plate chondrocyte; CL:0002519 Endocardial cushion mesenchyme (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Anatomical locations (UBERON terms) - UBERON:0003860 Growth plate of bone; UBERON:0002084 Atrioventricular canal; UBERON:0002080 Cardiac septum; UBERON:0001091 Tooth (caparrosmartin2013theciliaryevcevc2 pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
Chemical entities (CHEBI terms) - SAG (SMO agonist; CHEBI reference compound) used in ciliary Hh assays; MG132 (proteasome inhibitor) stabilizes hypomorphic WDR35Δ3 in vitro (experimental confirmation) (caparrosmartin2015specificvariantsin pages 4-5).
EvC Pathophysiology Summary (artifact) | Genes/Proteins | Role in EvC/Hh signaling (one sentence) | Pathway/Process (GO term names) | Cellular component | Phenotypes linked (HP term names) | Key evidence | Source URL | |---|---|---|---|---|---|---| | EVC | Membrane protein that localizes to the EvC zone and supports Hedgehog signal transduction required for GLI activation in chondrocytes. | Hedgehog signaling; chondrocyte proliferation and differentiation; protein stability | Primary cilium — EvC zone / ciliary base | Postaxial polydactyly; Short stature; Short ribs; Tooth anomalies; AV canal defect | (caparrosmartin2013theciliaryevcevc2 pages 1-2, barbeito2023evcevc2complexstability pages 2-4) | https://doi.org/10.1093/hmg/dds409, https://doi.org/10.3389/fcell.2023.1190258 | | EVC2 | Partner of EVC; its C‑terminal W‑peptide (FV motif and additional motifs) mediates EvC‑zone targeting and stabilizes the heterodimer to enable Hh transduction. | Hedgehog signaling; chondrocyte differentiation; protein ubiquitination; protein SUMOylation | Primary cilium — EvC zone; EVC2 cytosolic tail | Postaxial polydactyly; Short limbs; Dental/nail anomalies; Cardiac septation defects | (caparrosmartin2013theciliaryevcevc2 pages 1-2, barbeito2023evcevc2complexstability pages 2-4, louie2020molecularandcellular pages 3-5) | https://doi.org/10.1093/hmg/dds409, https://doi.org/10.3389/fcell.2023.1190258, https://doi.org/10.3390/jdb8040025 | | EVC–EVC2 complex | Heterodimer that binds Smoothened (SMO) at the ciliary base to promote SUFU/GLI dissociation and GLI trafficking to the ciliary tip, enabling GLI activator formation. | Hedgehog signaling; SUFU–GLI processing; intraflagellar transport | EvC zone (immediately distal to transition zone); ciliary base and proximal axoneme | Impaired endochondral ossification; Polydactyly; AV canal/common atrium | (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9, barbeito2023evcevc2complexstability pages 2-4) | https://doi.org/10.1093/hmg/dds409, https://doi.org/10.3389/fcell.2023.1190258 | | SMO (Smoothened) | Ciliary GPCR‑like effector that translocates into cilia and forms a functional complex with EVC/EVC2 to propagate Hh signals to GLI effectors. | Hedgehog signaling; intraflagellar transport | Ciliary membrane and EvC zone (ciliary base) | Cardiac septation defects (AVCD/VSD); Skeletal dysplasia | (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2015specificvariantsin pages 1-2) | https://doi.org/10.1093/hmg/dds409, https://doi.org/10.1093/hmg/ddv152 | | GLI3 / SUFU | GLI transcription factors are processed into repressors/activators; EVC–EVC2 promotes SUFU–GLI dissociation and GLI trafficking/activation at cilia, controlling Hh target gene expression. | Hedgehog signaling; GLI-mediated transcription; proteolytic processing | Ciliary tip (GLI accumulation), ciliary base (SUFU complex), nucleus | Reduced growth‑plate proliferation/hypertrophy; VSD/AV canal defects; skeletal anomalies | (caparrosmartin2013theciliaryevcevc2 pages 1-2, caparrosmartin2013theciliaryevcevc2 pages 7-9) | https://doi.org/10.1093/hmg/dds409 | | EFCAB7–IQCE tether | Tethers EVC–EVC2 to the EvC zone; required for proper EvC‑zone targeting and Hh signaling (SUMO3 enhances tethering; monoubiquitination reduces EVC–EVC2 levels). | Ciliary targeting; Hedgehog signaling; protein SUMOylation; protein ubiquitination | EvC zone / basal body interface (tether at ciliary base) | EvC skeletal/cardiac/dental phenotypes when disrupted | (barbeito2023evcevc2complexstability pages 2-4, barbeito2023evcevc2complexstability pages 1-2) | https://doi.org/10.3389/fcell.2023.1190258 | | WDR35 (IFT121) | IFT‑A component necessary for recruitment/entry of the EVC–EVC2 complex and SMO into the cilium; pathogenic variants prevent ciliary localization and phenocopy EvC Hh defects. | Intraciliary transport (IFT‑A); Hedgehog signaling | Intraflagellar transport complex A; ciliary shaft/base | Ellis‑van Creveld–like skeletal dysplasia; Polydactyly; Cardiac malformations | (caparrosmartin2015specificvariantsin pages 1-2, caparrosmartin2015specificvariantsin pages 4-5) | https://doi.org/10.1093/hmg/ddv152 |
Table: Compact summary table linking key genes/proteins to their mechanistic roles in Ellis‑van Creveld syndrome, relevant GO-like processes, subcellular localization, clinical phenotypes, and primary evidence (context IDs and DOI URLs) for rapid reference and knowledge‑base curation.
Limitations - While the 2023 study provides new regulatory insight (ubiquitin/SUMO), many foundational mechanistic data remain from 2012–2015, with fewer 2024 primary mechanistic updates specific to EvC identified here. Where possible, conclusions are triangulated across multiple sources (barbeito2023evcevc2complexstability pages 2-4, caparrosmartin2013theciliaryevcevc2 pages 7-9, caparrosmartin2013theciliaryevcevc2 pages 1-2).
Overall synthesis EvC pathogenesis centers on a ciliary signaling module—EVC/EVC2 at the EvC zone—that licenses SMO‑dependent GLI activation. Failures in complex assembly, targeting (EFCAB7–IQCE), or ciliary entry (WDR35/IFT‑A) attenuate Hh outputs in cartilage and heart, yielding the characteristic skeletal dysplasia and AV canal/common atrium. Post‑translational control by ubiquitination/SUMOylation further tunes complex stability and localization, presenting emerging mechanistic points that may inform future diagnostic assays or therapeutic hypotheses (caparrosmartin2013theciliaryevcevc2 pages 1-2, barbeito2023evcevc2complexstability pages 2-4, caparrosmartin2013theciliaryevcevc2 pages 7-9, caparrosmartin2015specificvariantsin pages 1-2, piceci‐sparascio2020commonatriumatrioventricularcanal pages 16-20).
References
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