👪

Inheritance

1

Autosomal Recessive

Autosomal recessive inheritance with genetic heterogeneity across IFT complex genes.

Show evidence (1 reference)

PMID:20817137 SUPPORT Human Clinical

"Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities."

Confirms autosomal recessive inheritance and the core craniosynostosis / ectodermal / skeletal triad of CED.

◆

Subtypes

4

CED1 (IFT122-associated)

Caused by biallelic mutations in IFT122 (WDR10), the first and most frequently mutated gene identified in CED. IFT122 encodes a component of the intraflagellar transport complex-A required for retrograde ciliary transport.

CED2 (WDR35-associated)

Caused by biallelic mutations in WDR35 (IFT121), an intraflagellar transport complex-A subunit. Identified through exome sequencing of sporadic CED patients.

CED3 (IFT43-associated)

Caused by biallelic mutations in IFT43 (C14orf179), a small intraflagellar transport complex-A subunit.

CED4 (WDR19-associated)

Caused by biallelic mutations in WDR19 (IFT144), an intraflagellar transport complex-A subunit that drives retrograde ciliary transport. WDR19 mutations also cause clinically overlapping skeletal ciliopathies (Jeune syndrome) and isolated nephronophthisis.

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Pathophysiology

4

Intraflagellar Transport Dysfunction

Biallelic mutations in IFT genes disrupt ciliary transport. Most CED genes encode IFT-A subunits involved in retrograde trafficking (IFT122, WDR35, IFT43, WDR19, and IFT140), while IFT52 encodes an IFT-B core subunit. Disrupted intraflagellar transport impairs primary cilium assembly, maintenance, and the gated compartmentalization of signaling machinery, producing a structurally deficient or functionally incompetent cilium.

ciliated cell CL:0000064

intraflagellar transport GO:0042073 ⚠ ABNORMAL retrograde intraflagellar transport GO:0035735 ↓ DECREASED cilium assembly GO:0060271 ↓ DECREASED

primary cilium GO:0005929

Downstream

Cilium-Dependent Signaling Failure A functionally incompetent primary cilium cannot correctly transduce cilium-dependent developmental signaling, principally Hedgehog and non-canonical Wnt / planar cell polarity.

Craniofacial, Skeletal, and Ectodermal Dysplasia Defective ciliary signaling during development disrupts cranial suture, skeletal, and ectodermal-appendage morphogenesis.

Renal-Hepatic-Retinal Ciliopathy Pleiotropy Ciliary dysfunction in renal tubular epithelium, hepatobiliary tissue, and photoreceptors produces the progressive multiorgan involvement of CED.

Show evidence (4 references)

PMID:20493458 SUPPORT Human Clinical

"Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls."

Establishes IFT122 as a CED gene and shows that its loss reduces primary cilium frequency and length in patient fibroblasts, anchoring the ciliary basis of the disorder.

PMID:22019273 SUPPORT Human Clinical

"WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport."

Identifies WDR19/IFT144 as an IFT-A subunit driving retrograde ciliary transport, the transport process disrupted in CED.

PMID:33517396 SUPPORT In Vitro

"Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140 and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED)."

Confirms that the IFT-A subunit genes, including all four classic CED genes plus IFT140, cause skeletal ciliopathies such as CED.

+ 1 more reference

Cilium-Dependent Signaling Failure

The primary cilium is the obligate organelle for vertebrate Hedgehog signal transduction and coordinates non-canonical Wnt / planar cell polarity (PCP) signaling. IFT-A-driven ciliary assembly and trafficking defects derange these pathways, perturbing the developmental signaling that patterns the skull, skeleton, and tubular organs.

Hedgehog (smoothened) signaling pathway GO:0007224 ↕ DYSREGULATED establishment of planar polarity GO:0001736 ⚠ ABNORMAL

Downstream

Craniofacial, Skeletal, and Ectodermal Dysplasia Disrupted cilium-dependent Hedgehog and PCP signaling in the developing cranium, growth plate, and ectodermal appendages produces the craniofacial, skeletal, and ectodermal phenotype.

Show evidence (1 reference)

PMID:33517396 SUPPORT In Vitro

"When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins."

Demonstrates that IFT-A (IFT144/WDR19) loss compromises ciliogenesis and the localization of ciliary proteins, the substrate for cilium-dependent signaling, in a cell model of CED genotypes.

Craniofacial, Skeletal, and Ectodermal Dysplasia

The developmental arm of CED. Impaired cilium-dependent signaling disturbs cranial suture patterning (producing sagittal craniosynostosis and dolichocephaly), endochondral skeletal growth (narrow thorax, short proximal limbs, brachydactyly, polydactyly), and the morphogenesis of ectodermal appendages (sparse hair, hypoplastic widely spaced teeth, abnormal nails). Dolichocephaly secondary to sagittal craniosynostosis is the manifestation that distinguishes CED from most other ciliopathies.

chondrocyte CL:0000138

bone morphogenesis GO:0060349 ⚠ ABNORMAL

thoracic rib cage UBERON:0003252

Downstream

Short stature

Joint hypermobility

Rhizomelia

Sagittal Craniosynostosis

Dolichocephaly

Frontal Bossing

Telecanthus

Narrow Thorax

Brachydactyly

Postaxial Polydactyly

Sparse Hair

Widely Spaced Teeth

Hypodontia

Abnormal Nails

Cutis Laxa

Show evidence (2 references)

PMID:24027799 SUPPORT Human Clinical

"Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth..."

The GeneReviews clinical summary enumerates the skeletal, ectodermal, and craniofacial features that constitute this developmental node.

PMID:24027799 SUPPORT Human Clinical

"Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies."

Identifies sagittal-craniosynostosis-driven dolichocephaly as the distinguishing craniofacial manifestation of CED.

Renal-Hepatic-Retinal Ciliopathy Pleiotropy

The degenerative multiorgan arm of CED. Ciliary dysfunction in renal tubular epithelium produces nephronophthisis that frequently progresses to end-stage kidney disease, the major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy reflect the same ciliopathy mechanism in hepatobiliary tissue and photoreceptors.

kidney tubule epithelial cell CL:0002518

kidney development GO:0001822 ⚠ ABNORMAL

kidney UBERON:0002113 liver UBERON:0002107

Downstream

Nephronophthisis

Hepatic Fibrosis

Retinal Dystrophy

Show evidence (2 references)

PMID:24027799 SUPPORT Human Clinical

"Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed."

Establishes nephronophthisis with progression to end-stage kidney disease, hepatic fibrosis, and retinal dystrophy as the multiorgan ciliopathy pleiotropy of CED.

PMID:32007091 SUPPORT Human Clinical

"Both patients had severe renal failure requiring kidney transplantation in early childhood."

Confirms early-onset, transplant-requiring renal failure in CED, supporting the severity of the renal arm.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

18

Digestive 1

Hepatic Fibrosis Hepatic fibrosis HP:0001395

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Hepatic fibrosis and retinal dystrophy are also observed."

Lists hepatic fibrosis among the multiorgan manifestations of CED.

Eye 1

Retinal Dystrophy Retinal dystrophy HP:0000556

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Hepatic fibrosis and retinal dystrophy are also observed."

Lists retinal dystrophy among the multiorgan manifestations of CED.

Genitourinary 1

Nephronophthisis VERY_FREQUENT Nephronophthisis HP:0000090

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality."

Establishes nephronophthisis in most affected children, progressing to end-stage kidney disease; supports both the VERY_FREQUENT band ("most affected children") and the progressive course.

Head and Neck 3

Sagittal Craniosynostosis Sagittal craniosynostosis HP:0004442

Show evidence (1 reference)

PMID:20817137 SUPPORT Human Clinical

"Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities."

Identifies craniosynostosis as a defining feature of CED.

Frontal Bossing Frontal bossing HP:0002007

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)"

Lists frontal bossing among the characteristic CED facial features.

Hypodontia Hypodontia HP:0000668

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails)"

Lists hypodontia among the ectodermal features of CED.

Integument 3

Sparse Hair Sparse hair HP:0008070

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails)"

Lists sparse hair among the ectodermal features of CED.

Abnormal Nails Abnormal nail morphology HP:0001597

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails)"

Lists abnormal nails among the ectodermal features of CED.

Cutis Laxa Cutis laxa HP:0000973

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails)"

Lists skin laxity among the ectodermal features of CED.

Limbs 2

Brachydactyly Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly)"

Lists brachydactyly among the skeletal features of CED.

Postaxial Polydactyly Postaxial polydactyly HP:0100259

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly)"

Lists polydactyly among the skeletal features of CED.

Musculoskeletal 2

Joint hypermobility Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"joint laxity"

GeneReviews lists joint laxity among the core clinical characteristics of cranioectodermal dysplasia.

Narrow Thorax Narrow chest HP:0000774

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly)"

Lists narrow thorax among the skeletal features of CED.

Growth 2

Short stature Short stature HP:0004322

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"growth deficiency, and characteristic facial features"

GeneReviews lists growth deficiency among the core clinical characteristics of cranioectodermal dysplasia.

Rhizomelia Rhizomelia HP:0008905

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"shortened proximal limbs, syndactyly"

GeneReviews lists shortened proximal limbs (rhizomelia) within the skeletal involvement of cranioectodermal dysplasia.

Other 3

Dolichocephaly Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies."

Establishes dolichocephaly as a primary, distinguishing manifestation of CED.

Telecanthus Telecanthus HP:0000506

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)"

Lists telecanthus among the characteristic CED facial features.

Widely Spaced Teeth Widely spaced teeth HP:0000687

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails)"

Lists widely spaced hypoplastic teeth among the ectodermal features of CED.

🧬

Genetic Associations

6

IFT122 (Causative)

Gene: IFT122 hgnc:13556 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:20493458 SUPPORT Human Clinical

"Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene."

Landmark paper establishing IFT122 as the first identified CED gene (CED1).

WDR35 (Causative)

Gene: WDR35 hgnc:29250 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:20817137 SUPPORT Human Clinical

"We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently"

Establishes WDR35 as a CED gene (CED2) via exome sequencing of unrelated patients.

IFT43 (Causative)

Gene: IFT43 hgnc:29669 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"identification of biallelic pathogenic variants in one of the six genes currently known to be associated with CED: IFT43, IFT52, IFT122, IFT140, WDR19, or WDR35."

GeneReviews lists IFT43 among the genes in which biallelic pathogenic variants establish a molecular diagnosis of CED (CED3).

WDR19 (Causative)

Gene: WDR19 hgnc:18340 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:22019273 SUPPORT Human Clinical

"Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome."

Establishes WDR19 (IFT144) as a CED gene (CED4) in a family with Sensenbrenner syndrome.

IFT140 (Causative)

Gene: IFT140 hgnc:29077 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (2 references)

PMID:32007091 SUPPORT Human Clinical

"The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome."

Direct CED case evidence supports IFT140 as a causative cranioectodermal dysplasia gene.

PMID:32007091 SUPPORT Human Clinical

"Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele."

Highlights that IFT140-associated CED can involve a tandem duplication requiring copy-number-aware molecular testing.

IFT52 (Causative)

Gene: IFT52 hgnc:15901 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"identification of biallelic pathogenic variants in one of the six genes currently known to be associated with CED: IFT43, IFT52, IFT122, IFT140, WDR19, or WDR35."

GeneReviews includes IFT52 among the six genes in which biallelic pathogenic variants establish molecular diagnosis of CED.

💊

Medical Actions

4

Craniosynostosis Surgery

Action: surgical procedure MAXO:0000004

Surgical correction of sagittal craniosynostosis, usually performed before age one year, to relieve premature suture fusion and its sequelae.

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"As needed, surgery to correct sagittal craniosynostosis usually before age one year."

GeneReviews recommends surgical correction of sagittal craniosynostosis, usually before age one year.

Kidney Transplantation

Action: whole kidney transplantation MAXO:0010043

Kidney transplantation for end-stage kidney disease from progressive nephronophthisis, frequently required in infancy or childhood.

Show evidence (1 reference)

PMID:32007091 SUPPORT Human Clinical

"Both patients had severe renal failure requiring kidney transplantation in early childhood."

Documents kidney transplantation in early childhood for CED-associated renal failure.

Growth Hormone Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: recombinant human growth hormone NCIT:C164163

Human growth hormone therapy could be considered in individuals who meet standard treatment criteria for growth deficiency.

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"Human growth hormone therapy could be considered in those who meet standard treatment criteria."

GeneReviews notes human growth hormone therapy may be considered for growth deficiency in CED.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

CED is inherited in an autosomal recessive manner; genetic counseling supports families with recurrence-risk assessment, carrier testing, and prenatal or preimplantation testing once the family variants are known.

Show evidence (1 reference)

PMID:24027799 SUPPORT Human Clinical

"CED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected"

Supports genetic counseling for recurrence-risk assessment given autosomal recessive inheritance.

{ }

Source YAML

click to show

name: Cranioectodermal Dysplasia
creation_date: "2026-06-17T00:00:00Z"
category: Mendelian
description: >
  Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a
  rare autosomal recessive skeletal ciliopathy characterized by craniofacial,
  skeletal, and ectodermal anomalies (dolichocephaly often secondary to sagittal
  craniosynostosis, narrow thorax, shortened proximal limbs, brachydactyly,
  polydactyly, sparse hair, widely spaced hypoplastic teeth, and abnormal nails),
  frequently complicated by nephronophthisis-type progressive renal failure,
  hepatic fibrosis, and retinal dystrophy. CED is caused by biallelic mutations in
  genes encoding intraflagellar transport (IFT) components. The four
  classically recognized molecular subtypes are CED1 (IFT122), CED2 (WDR35),
  CED3 (IFT43), and CED4 (WDR19); additional IFT genes (IFT140, IFT52) have
  since been associated with the syndrome. Loss of IFT function disrupts ciliary
  transport and primary cilium function, converging on the
  shared ciliopathy mechanism.
disease_term:
  preferred_term: cranioectodermal dysplasia
  term:
    id: MONDO:0009032
    label: cranioectodermal dysplasia
parents:
- Ciliopathies
references:
- reference: PMID:24027799
  title: "Cranioectodermal Dysplasia"
  tags:
  - GeneReviews
has_subtypes:
- name: CED1
  display_name: CED1 (IFT122-associated)
  description: >
    Caused by biallelic mutations in IFT122 (WDR10), the first and most frequently
    mutated gene identified in CED. IFT122 encodes a component of the intraflagellar
    transport complex-A required for retrograde ciliary transport.
- name: CED2
  display_name: CED2 (WDR35-associated)
  description: >
    Caused by biallelic mutations in WDR35 (IFT121), an intraflagellar transport
    complex-A subunit. Identified through exome sequencing of sporadic CED patients.
- name: CED3
  display_name: CED3 (IFT43-associated)
  description: >
    Caused by biallelic mutations in IFT43 (C14orf179), a small intraflagellar
    transport complex-A subunit.
- name: CED4
  display_name: CED4 (WDR19-associated)
  description: >
    Caused by biallelic mutations in WDR19 (IFT144), an intraflagellar transport
    complex-A subunit that drives retrograde ciliary transport. WDR19 mutations
    also cause clinically overlapping skeletal ciliopathies (Jeune syndrome) and
    isolated nephronophthisis.
inheritance:
- name: Autosomal Recessive
  description: >
    Autosomal recessive inheritance with genetic heterogeneity across IFT
    complex genes.
  evidence:
  - reference: PMID:20817137
    reference_title: "Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an
      autosomal-recessive disease that is characterized by craniosynostosis and
      ectodermal and skeletal abnormalities.
    explanation: >-
      Confirms autosomal recessive inheritance and the core craniosynostosis /
      ectodermal / skeletal triad of CED.
prevalence:
- population: General population
  notes: >-
    CED is a rare disorder; fewer than 100 affected individuals had been reported
    in the literature at the time of the GeneReviews summary, with no precise
    incidence established.
pathophysiology:
- name: Intraflagellar Transport Dysfunction
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >
    Biallelic mutations in IFT genes disrupt ciliary transport. Most CED genes
    encode IFT-A subunits involved in retrograde trafficking (IFT122, WDR35,
    IFT43, WDR19, and IFT140), while IFT52 encodes an IFT-B core subunit.
    Disrupted intraflagellar transport impairs primary cilium assembly,
    maintenance, and the gated compartmentalization of signaling machinery,
    producing a structurally deficient or functionally incompetent cilium.
  cell_types:
  - preferred_term: ciliated cell
    term:
      id: CL:0000064
      label: ciliated cell
  biological_processes:
  - preferred_term: intraflagellar transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: ABNORMAL
  - preferred_term: retrograde intraflagellar transport
    term:
      id: GO:0035735
      label: intraciliary transport involved in cilium assembly
    modifier: DECREASED
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:20493458
    reference_title: "Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because IFT122 plays an important role in the assembly and maintenance of
      eukaryotic cilia, we investigated patient fibroblasts and found
      significantly reduced frequency and length of primary cilia as compared to
      controls.
    explanation: >-
      Establishes IFT122 as a CED gene and shows that its loss reduces primary
      cilium frequency and length in patient fibroblasts, anchoring the ciliary
      basis of the disorder.
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WDR19 encodes IFT144, a member of the intraflagellar transport (IFT)
      complex A that drives retrograde ciliary transport.
    explanation: >-
      Identifies WDR19/IFT144 as an IFT-A subunit driving retrograde ciliary
      transport, the transport process disrupted in CED.
  - reference: PMID:33517396
    reference_title: "Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35,
      IFT122, IFT139/TTC21B, IFT140 and IFT144/WDR19) often result in skeletal
      ciliopathies, including cranioectodermal dysplasia (CED).
    explanation: >-
      Confirms that the IFT-A subunit genes, including all four classic CED
      genes plus IFT140, cause skeletal ciliopathies such as CED.
  - reference: PMID:27666822
    reference_title: "Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IFT52 is another key member of the core complex, and forms a trimeric
      complex with IFT70 and IFT88
    explanation: >-
      Establishes IFT52 as an IFT-B core-complex subunit, correcting the
      mechanism label for the IFT52-associated CED gene.
  downstream:
  - target: Cilium-Dependent Signaling Failure
    description: >-
      A functionally incompetent primary cilium cannot correctly transduce
      cilium-dependent developmental signaling, principally Hedgehog and
      non-canonical Wnt / planar cell polarity.
    causal_link_type: DIRECT
  - target: Craniofacial, Skeletal, and Ectodermal Dysplasia
    description: >-
      Defective ciliary signaling during development disrupts cranial suture,
      skeletal, and ectodermal-appendage morphogenesis.
    causal_link_type: DIRECT
  - target: Renal-Hepatic-Retinal Ciliopathy Pleiotropy
    description: >-
      Ciliary dysfunction in renal tubular epithelium, hepatobiliary tissue, and
      photoreceptors produces the progressive multiorgan involvement of CED.
    causal_link_type: DIRECT
- name: Cilium-Dependent Signaling Failure
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >
    The primary cilium is the obligate organelle for vertebrate Hedgehog signal
    transduction and coordinates non-canonical Wnt / planar cell polarity (PCP)
    signaling. IFT-A-driven ciliary assembly and trafficking defects derange these
    pathways, perturbing the developmental signaling that patterns the skull,
    skeleton, and tubular organs.
  biological_processes:
  - preferred_term: Hedgehog (smoothened) signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  - preferred_term: establishment of planar polarity
    term:
      id: GO:0001736
      label: establishment of planar polarity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33517396
    reference_title: "Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as
      well as IFT144(WT) rescued both moderately compromised ciliogenesis and the
      abnormal localization of ciliary proteins.
    explanation: >-
      Demonstrates that IFT-A (IFT144/WDR19) loss compromises ciliogenesis and the
      localization of ciliary proteins, the substrate for cilium-dependent
      signaling, in a cell model of CED genotypes.
  downstream:
  - target: Craniofacial, Skeletal, and Ectodermal Dysplasia
    description: >-
      Disrupted cilium-dependent Hedgehog and PCP signaling in the developing
      cranium, growth plate, and ectodermal appendages produces the craniofacial,
      skeletal, and ectodermal phenotype.
    causal_link_type: DIRECT
- name: Craniofacial, Skeletal, and Ectodermal Dysplasia
  description: >
    The developmental arm of CED. Impaired cilium-dependent signaling disturbs
    cranial suture patterning (producing sagittal craniosynostosis and
    dolichocephaly), endochondral skeletal growth (narrow thorax, short proximal
    limbs, brachydactyly, polydactyly), and the morphogenesis of ectodermal
    appendages (sparse hair, hypoplastic widely spaced teeth, abnormal nails).
    Dolichocephaly secondary to sagittal craniosynostosis is the manifestation
    that distinguishes CED from most other ciliopathies.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  locations:
  - preferred_term: thoracic rib cage
    term:
      id: UBERON:0003252
      label: thoracic rib cage
  biological_processes:
  - preferred_term: bone morphogenesis
    term:
      id: GO:0060349
      label: bone morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement
      (narrow thorax, shortened proximal limbs, syndactyly, polydactyly,
      brachydactyly), ectodermal features (widely spaced hypoplastic teeth,
      hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth
      deficiency, and characteristic facial features
    explanation: >-
      The GeneReviews clinical summary enumerates the skeletal, ectodermal, and
      craniofacial features that constitute this developmental node.
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary
      manifestation that distinguishes CED from most other ciliopathies.
    explanation: >-
      Identifies sagittal-craniosynostosis-driven dolichocephaly as the
      distinguishing craniofacial manifestation of CED.
  downstream:
  - target: Short stature
  - target: Joint hypermobility
  - target: Rhizomelia
  - target: Sagittal Craniosynostosis
  - target: Dolichocephaly
  - target: Frontal Bossing
  - target: Telecanthus
  - target: Narrow Thorax
  - target: Brachydactyly
  - target: Postaxial Polydactyly
  - target: Sparse Hair
  - target: Widely Spaced Teeth
  - target: Hypodontia
  - target: Abnormal Nails
  - target: Cutis Laxa
- name: Renal-Hepatic-Retinal Ciliopathy Pleiotropy
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  description: >
    The degenerative multiorgan arm of CED. Ciliary dysfunction in renal tubular
    epithelium produces nephronophthisis that frequently progresses to end-stage
    kidney disease, the major cause of morbidity and mortality. Hepatic fibrosis
    and retinal dystrophy reflect the same ciliopathy mechanism in hepatobiliary
    tissue and photoreceptors.
  cell_types:
  - preferred_term: kidney tubule epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected children develop nephronophthisis that often leads to
      end-stage kidney disease in infancy or childhood, a major cause of morbidity
      and mortality. Hepatic fibrosis and retinal dystrophy are also observed.
    explanation: >-
      Establishes nephronophthisis with progression to end-stage kidney disease,
      hepatic fibrosis, and retinal dystrophy as the multiorgan ciliopathy
      pleiotropy of CED.
  - reference: PMID:32007091
    reference_title: "Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had severe renal failure requiring kidney transplantation in
      early childhood.
    explanation: >-
      Confirms early-onset, transplant-requiring renal failure in CED, supporting
      the severity of the renal arm.
  downstream:
  - target: Nephronophthisis
  - target: Hepatic Fibrosis
  - target: Retinal Dystrophy
phenotypes:
- name: Short stature
  description: >
    Growth deficiency / short stature is a core clinical feature of CED.
  phenotype_term:
    preferred_term: Growth deficiency
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth deficiency, and characteristic facial features
    explanation: >-
      GeneReviews lists growth deficiency among the core clinical
      characteristics of cranioectodermal dysplasia.
- name: Joint hypermobility
  description: >
    Generalized joint laxity is a recognized core feature of CED.
  phenotype_term:
    preferred_term: Joint laxity
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      joint laxity
    explanation: >-
      GeneReviews lists joint laxity among the core clinical characteristics of
      cranioectodermal dysplasia.
- name: Rhizomelia
  description: >
    Shortened proximal limbs (rhizomelic limb shortening) are part of the
    skeletal involvement in CED.
  phenotype_term:
    preferred_term: Shortened proximal limbs
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      shortened proximal limbs, syndactyly
    explanation: >-
      GeneReviews lists shortened proximal limbs (rhizomelia) within the
      skeletal involvement of cranioectodermal dysplasia.
- name: Sagittal Craniosynostosis
  description: >
    Premature fusion of the sagittal suture producing dolichocephaly, the
    craniofacial feature that distinguishes CED from most other ciliopathies.
  phenotype_term:
    preferred_term: Sagittal craniosynostosis
    term:
      id: HP:0004442
      label: Sagittal craniosynostosis
  evidence:
  - reference: PMID:20817137
    reference_title: "Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an
      autosomal-recessive disease that is characterized by craniosynostosis and
      ectodermal and skeletal abnormalities.
    explanation: >-
      Identifies craniosynostosis as a defining feature of CED.
- name: Dolichocephaly
  description: >
    Long, narrow head shape, typically secondary to sagittal craniosynostosis;
    a primary manifestation of CED.
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary
      manifestation that distinguishes CED from most other ciliopathies.
    explanation: >-
      Establishes dolichocephaly as a primary, distinguishing manifestation of CED.
- name: Frontal Bossing
  description: >
    Prominent forehead, part of the characteristic CED facial gestalt.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characteristic facial features (frontal bossing, low-set simple ears, high
      forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
    explanation: >-
      Lists frontal bossing among the characteristic CED facial features.
- name: Telecanthus
  description: >
    Increased distance between the inner canthi, part of the CED facial gestalt.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characteristic facial features (frontal bossing, low-set simple ears, high
      forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip)
    explanation: >-
      Lists telecanthus among the characteristic CED facial features.
- name: Narrow Thorax
  description: >
    Narrow thorax with short ribs contributing to respiratory compromise; part of
    the skeletal ciliopathy phenotype, which may require mechanical ventilation in
    newborns with pulmonary hypoplasia.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement
      (narrow thorax, shortened proximal limbs, syndactyly, polydactyly,
      brachydactyly)
    explanation: >-
      Lists narrow thorax among the skeletal features of CED.
- name: Brachydactyly
  description: >
    Shortening of the digits, part of the skeletal involvement in CED.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly,
      polydactyly, brachydactyly)
    explanation: >-
      Lists brachydactyly among the skeletal features of CED.
- name: Postaxial Polydactyly
  description: >
    Extra digits on the ulnar/fibular side of the limb, present in a subset of
    CED patients.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly,
      polydactyly, brachydactyly)
    explanation: >-
      Lists polydactyly among the skeletal features of CED.
- name: Sparse Hair
  category: Ectodermal
  description: >
    Sparse, slow-growing hair, a cardinal ectodermal feature of CED.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse
      hair, skin laxity, abnormal nails)
    explanation: >-
      Lists sparse hair among the ectodermal features of CED.
- name: Widely Spaced Teeth
  category: Ectodermal
  description: >
    Widely spaced, hypoplastic teeth, an ectodermal feature of CED.
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse
      hair, skin laxity, abnormal nails)
    explanation: >-
      Lists widely spaced hypoplastic teeth among the ectodermal features of CED.
- name: Hypodontia
  category: Ectodermal
  description: >
    Congenital absence of teeth, an ectodermal feature of CED.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse
      hair, skin laxity, abnormal nails)
    explanation: >-
      Lists hypodontia among the ectodermal features of CED.
- name: Abnormal Nails
  category: Ectodermal
  description: >
    Abnormal nail morphology, an ectodermal feature of CED.
  phenotype_term:
    preferred_term: Abnormal nail morphology
    term:
      id: HP:0001597
      label: Abnormal nail morphology
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse
      hair, skin laxity, abnormal nails)
    explanation: >-
      Lists abnormal nails among the ectodermal features of CED.
- name: Cutis Laxa
  category: Ectodermal
  description: >
    Skin laxity, an ectodermal/connective-tissue feature of CED.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse
      hair, skin laxity, abnormal nails)
    explanation: >-
      Lists skin laxity among the ectodermal features of CED.
- name: Nephronophthisis
  description: >
    Most affected children develop nephronophthisis, frequently progressing to
    end-stage kidney disease in infancy or childhood, the major cause of morbidity
    and mortality in CED.
  phenotype_term:
    preferred_term: Nephronophthisis
    term:
      id: HP:0000090
      label: Nephronophthisis
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected children develop nephronophthisis that often leads to
      end-stage kidney disease in infancy or childhood, a major cause of morbidity
      and mortality.
    explanation: >-
      Establishes nephronophthisis in most affected children, progressing to
      end-stage kidney disease; supports both the VERY_FREQUENT band ("most
      affected children") and the progressive course.
- name: Hepatic Fibrosis
  description: >
    Hepatic fibrosis as part of the hepatobiliary ciliopathy spectrum of CED.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatic fibrosis and retinal dystrophy are also observed.
    explanation: >-
      Lists hepatic fibrosis among the multiorgan manifestations of CED.
- name: Retinal Dystrophy
  description: >
    Retinal dystrophy/degeneration as part of the ciliopathy phenotype of CED.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatic fibrosis and retinal dystrophy are also observed.
    explanation: >-
      Lists retinal dystrophy among the multiorgan manifestations of CED.
genetic:
- name: IFT122
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: IFT122
    term:
      id: hgnc:13556
      label: IFT122
  subtype: CED1
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:20493458
    reference_title: "Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused
      by mutations in the IFT122 gene.
    explanation: >-
      Landmark paper establishing IFT122 as the first identified CED gene (CED1).
- name: WDR35
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: WDR35
    term:
      id: hgnc:29250
      label: WDR35
  subtype: CED2
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:20817137
    reference_title: "Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the exomes of two unrelated CED patients and identified
      compound heterozygous mutations in WDR35 as the cause of the disease in each
      of the two patients independently
    explanation: >-
      Establishes WDR35 as a CED gene (CED2) via exome sequencing of unrelated
      patients.
- name: IFT43
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: IFT43
    term:
      id: hgnc:29669
      label: IFT43
  subtype: CED3
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification of biallelic pathogenic variants in one of the six genes
      currently known to be associated with CED: IFT43, IFT52, IFT122, IFT140,
      WDR19, or WDR35.
    explanation: >-
      GeneReviews lists IFT43 among the genes in which biallelic pathogenic
      variants establish a molecular diagnosis of CED (CED3).
- name: WDR19
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: WDR19
    term:
      id: hgnc:18340
      label: WDR19
  subtype: CED4
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through exome sequencing we identified compound heterozygous mutations in
      WDR19 in a Norwegian family with Sensenbrenner syndrome.
    explanation: >-
      Establishes WDR19 (IFT144) as a CED gene (CED4) in a family with
      Sensenbrenner syndrome.
- name: IFT140
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:32007091
    reference_title: "Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The finding of compound heterozygous IFT140 mutations in two unrelated CED
      patients provide further evidence that IFT140 gene mutations are associated
      with this syndrome.
    explanation: >-
      Direct CED case evidence supports IFT140 as a causative cranioectodermal
      dysplasia gene.
  - reference: PMID:32007091
    reference_title: "Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup
      on one allele.
    explanation: >-
      Highlights that IFT140-associated CED can involve a tandem duplication
      requiring copy-number-aware molecular testing.
- name: IFT52
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: IFT52
    term:
      id: hgnc:15901
      label: IFT52
  inheritance:
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification of biallelic pathogenic variants in one of the six genes
      currently known to be associated with CED: IFT43, IFT52, IFT122, IFT140,
      WDR19, or WDR35.
    explanation: >-
      GeneReviews includes IFT52 among the six genes in which biallelic
      pathogenic variants establish molecular diagnosis of CED.
diagnosis:
- name: Clinical and Radiographic Diagnosis
  description: >-
    CED can be established clinically when the characteristic craniofacial,
    skeletal, ectodermal, and radiographic pattern is present, including at least
    two frequent features and two additional abnormalities with at least one
    ectodermal defect involving teeth, hair, or nails.
  diagnosis_term:
    preferred_term: clinical imaging procedure
    term:
      id: MAXO:0000005
      label: clinical imaging procedure
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of CED is established in a proband with characteristic
      clinical and radiographic features (including two frequent features and two
      other abnormalities, with at least one ectodermal defect – i.e.,
      involvement of the teeth, hair, or nails)
    explanation: >-
      GeneReviews defines the clinical/radiographic diagnostic rule for CED.
- name: Molecular Genetic Confirmation
  description: >-
    Molecular confirmation is by identifying biallelic pathogenic variants in a
    known CED gene: IFT43, IFT52, IFT122, IFT140, WDR19, or WDR35. Testing should
    be capable of detecting copy-number or structural alleles when sequence
    analysis finds only one variant, especially in IFT140.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification of biallelic pathogenic variants in one of the six genes
      currently known to be associated with CED: IFT43, IFT52, IFT122, IFT140,
      WDR19, or WDR35.
    explanation: >-
      GeneReviews gives the current six-gene molecular diagnostic criterion.
  - reference: PMID:32007091
    reference_title: "Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequent qPCR and duplex PCR analysis were conducted for both patients.
      Genetic analyses identified compound heterozygous variants in the IFT140
      gene in both affected individuals.
    explanation: >-
      The IFT140 case series shows that orthogonal copy-number assays were
      required in addition to NGS to resolve compound heterozygous variants.
- name: Prenatal Testing and Ultrasound in At-Risk Pregnancies
  description: >-
    Once familial pathogenic variants are known, prenatal or preimplantation
    genetic testing can be offered; second-trimester ultrasound may detect renal
    cysts, limb shortening, or polydactyly in an at-risk fetus.
  diagnosis_term:
    preferred_term: clinical imaging procedure
    term:
      id: MAXO:0000005
      label: clinical imaging procedure
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carrier testing for at-risk relatives, prenatal testing for a pregnancy at
      increased risk, and preimplantation genetic testing are possible once the
      CED-causing pathogenic variants have been identified in an affected family
      member.
    explanation: >-
      GeneReviews supports variant-informed prenatal and preimplantation
      testing in at-risk families.
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second-trimester ultrasound examination may detect renal cysts, shortening
      of the limbs, and/or polydactyly.
    explanation: >-
      GeneReviews supports second-trimester ultrasound as a prenatal diagnostic
      adjunct in at-risk pregnancies.
treatments:
- name: Craniosynostosis Surgery
  description: >
    Surgical correction of sagittal craniosynostosis, usually performed before
    age one year, to relieve premature suture fusion and its sequelae.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As needed, surgery to correct sagittal craniosynostosis usually before age
      one year.
    explanation: >-
      GeneReviews recommends surgical correction of sagittal craniosynostosis,
      usually before age one year.
- name: Kidney Transplantation
  description: >
    Kidney transplantation for end-stage kidney disease from progressive
    nephronophthisis, frequently required in infancy or childhood.
  treatment_term:
    preferred_term: whole kidney transplantation
    term:
      id: MAXO:0010043
      label: whole kidney transplantation
  evidence:
  - reference: PMID:32007091
    reference_title: "Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had severe renal failure requiring kidney transplantation in
      early childhood.
    explanation: >-
      Documents kidney transplantation in early childhood for CED-associated renal
      failure.
- name: Growth Hormone Therapy
  description: >
    Human growth hormone therapy could be considered in individuals who meet
    standard treatment criteria for growth deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant human growth hormone
      term:
        id: NCIT:C164163
        label: Therapeutic Growth Hormone
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human growth hormone therapy could be considered in those who meet standard
      treatment criteria.
    explanation: >-
      GeneReviews notes human growth hormone therapy may be considered for growth
      deficiency in CED.
- name: Genetic Counseling
  description: >
    CED is inherited in an autosomal recessive manner; genetic counseling supports
    families with recurrence-risk assessment, carrier testing, and prenatal or
    preimplantation testing once the family variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24027799
    reference_title: "Cranioectodermal Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CED is inherited in an autosomal recessive manner. If both parents are known
      to be heterozygous for a CED-causing pathogenic variant, each sib of an
      affected individual has at conception a 25% chance of being affected
    explanation: >-
      Supports genetic counseling for recurrence-risk assessment given autosomal
      recessive inheritance.

📚

References & Deep Research

References

1

PMID:24027799

Cranioectodermal Dysplasia

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 24 citations 2026-06-17T11:55:29.676125

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.

Disease Characteristics Research Template

Target Disease

Disease Name: Cranioectodermal Dysplasia
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Cranioectodermal Dysplasia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Cranioectodermal Dysplasia (CED) / Sensenbrenner syndrome

Executive summary

Cranioectodermal dysplasia (CED), also called Sensenbrenner syndrome, is an autosomal-recessive skeletal ciliopathy characterized by distinctive craniofacial findings (often craniosynostosis/dolichocephaly), skeletal dysplasia with a narrow thorax/short limbs, ectodermal anomalies (hair/nails/teeth), and variable multisystem involvement—most importantly progressive kidney disease and sometimes liver and ocular disease. Foundational gene-discovery studies established CED as an intraflagellar transport (IFT) disorder, with multiple causal genes in the IFT-A (retrograde transport) pathway and related ciliary trafficking processes. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)

1. Disease information

1.1 Overview / definition (current understanding)

CED is a rare, syndromic disorder in the ciliopathy spectrum. Classic clinical description includes craniosynostosis/dolichocephaly plus ectodermal and skeletal abnormalities, with frequent renal involvement (nephronophthisis/CKD) and possible hepatic fibrosis/cysts and retinal disease. (gilissen2010exomesequencingidentifies pages 1-2, hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, NCT04184531 chunk 1, li2023novelcompoundheterozygous pages 1-3)

Direct abstract quote (2020; Orphanet Journal of Rare Diseases): “Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition.” (Walczak-Sztulpa et al., 2020-02; https://doi.org/10.1186/s13023-020-1303-2) (walczaksztulpa2020compoundheterozygousift140 pages 1-2)

1.2 Key identifiers

MONDO: MONDO_0009032 (Open Targets disease page indexing) (OpenTargets Search: Cranioectodermal dysplasia,Sensenbrenner syndrome)
OMIM (disease): 218330 (CED / Sensenbrenner syndrome) (hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

Not retrieved in the current evidence set (therefore not asserted here): Orphanet disease identifier (ORPHA), MeSH identifier, ICD-10/ICD-11 code(s).

1.3 Synonyms / alternative names

Cranioectodermal dysplasia (CED) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2)
Sensenbrenner syndrome (gilissen2010exomesequencingidentifies pages 1-2, walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2)

1.4 Evidence type note

Most CED knowledge is derived from aggregated disease-level resources and cohort/case-series publications (e.g., AJHG gene discovery cohorts) and individual patient case reports describing new genotypes/phenotypes and diagnostic workflows, rather than EHR-derived population-level datasets in the provided evidence. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 1-2)

2. Etiology

2.1 Disease causal factors

CED is primarily a genetic ciliopathy caused by biallelic pathogenic variants in genes required for intraflagellar transport (IFT) and ciliary function. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, walczaksztulpa2020compoundheterozygousift140 pages 1-2)

Genetic heterogeneity is well-supported: the initial IFT122 cohort already noted not all patients carried IFT122 variants. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

2.2 Risk factors

Genetic risk factor: Having biallelic pathogenic variants in established CED genes (see Section 4). (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 1-2)
Family history/consanguinity: Many reported cases occur in families consistent with autosomal recessive inheritance; however, population-level risk quantification is not available in the retrieved evidence. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, walczaksztulpa2020compoundheterozygousift140 pages 1-2)

2.3 Protective factors / gene–environment interactions

No protective factors or gene–environment interactions were identified in the retrieved primary literature excerpts; CED is treated here as a primarily Mendelian disorder. (walczaksztulpa2020compoundheterozygousift140 pages 1-2)

3. Phenotypes (clinical spectrum)

3.1 Core phenotype domains and HPO suggestions

The table below consolidates the major phenotype domains and HPO term suggestions supported by the retrieved evidence.

Category	Item	Inheritance / role	Supported details	Example variants / detection notes	Example ontology terms	Evidence
Gene	IFT122	Autosomal recessive; IFT-A / retrograde intraflagellar transport	First CED gene identified; 13 patients from 12 families analyzed in the 2010 AJHG study; reduced frequency and length of primary cilia in patient fibroblasts; not all patients carried IFT122 variants, supporting genetic heterogeneity	Homozygous missense and compound heterozygous splice-site + missense genotypes reported; variants absent in 340 control chromosomes	GO:0030990 intraciliary transport particle A; GO:0005929 cilium	(walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)
Gene	WDR35 (IFT121)	Autosomal recessive; IFT-A / retrograde intraflagellar transport	Independently identified by exome sequencing in two unrelated patients; CED described with craniosynostosis plus ectodermal and skeletal abnormalities; WDR35 defects underlie a subset of CED and can be associated with severe renal disease	c.25-2A>G (p.I9TfsX7), c.1877A>G (p.E626G), c.2891delC (p.P964Lfs15), c.2623G>A (p.A875T); additional reported variants include c.2912A>G (p.Tyr971Cys), c.504T>A (p.Ser168Arg), c.1922T>G (p.Leu641), c.2590C>T (p.Gln864*), c.2408_2416del (p.Asn803_Ala805del); RT-PCR used to confirm splicing effect in one study	GO:0030990 intraciliary transport particle A; GO:0005929 cilium	(gilissen2010exomesequencingidentifies pages 1-2, hoffer2013novelwdr35mutations pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, li2023novelcompoundheterozygous pages 1-3)
Gene	IFT140	Autosomal recessive; IFT-A / retrograde intraflagellar transport	Rare cause of CED; both 2020 and 2023 reports emphasize early-onset renal failure/ESRD in some patients; 2023 report states only four patients had previously been described with this cranioectodermal phenotype	c.326T>C (p.Leu109Pro), c.1565G>A (p.Gly522Glu), c.2767_2768+2del, and recurrent tandem duplication c.3454-488_4182+2588dup (p.Tyr1152_Thr1394dup); duplication may be missed by standard NGS and required coverage/CNV analysis plus qPCR, duplex or multiplex PCR, breakpoint Sanger sequencing, and in one case WGS	GO:0030990 intraciliary transport particle A; GO:0005929 cilium	(walczaksztulpa2020compoundheterozygousift140 pages 4-6, walczaksztulpa2020compoundheterozygousift140 pages 1-2, sharova2023rareift140associatedphenotype pages 4-5, sharova2023rareift140associatedphenotype pages 1-2, sharova2023rareift140associatedphenotype pages 2-4)
Gene	IFT43	Autosomal recessive; gene listed among six established CED genes; IFT-related ciliopathy gene	Included in updated six-gene CED set in 2020 and 2023 sources; no specific patient-level variant examples were provided in the supplied snippets	No exemplar variant available in provided evidence snippets	GO:0005929 cilium	(walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Gene	WDR19	Autosomal recessive; gene listed among six established CED genes; IFT-A complex member in 2013 summary	Included in updated six-gene CED set; cited among previously reported causal genes in 2013 Clinical Genetics summary	No exemplar variant available in provided evidence snippets	GO:0030990 intraciliary transport particle A; GO:0005929 cilium	(hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Gene	IFT52	Autosomal recessive; gene listed among six established CED genes; IFT-related ciliopathy gene	Included in updated six-gene CED set in 2020 and 2023 sources	No exemplar variant available in provided evidence snippets	GO:0005929 cilium	(walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Phenotype domain	Craniofacial	Congenital/early childhood; often recognizable clinically	Dolichocephaly, frontal bossing, low-set ears, sagittal craniosynostosis, brachycephaly, epicanthus, short neck; craniofacial pattern is a major diagnostic clue	Often prompts surgical/craniofacial evaluation; one IFT140 case underwent vault remodeling at 7 months	HP:0000268 Dolichocephaly; HP:0002007 Frontal bossing; HP:0006114 Sagittal craniosynostosis; HP:0000248 Brachycephaly; HP:0000286 Epicanthus	(hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 4-5, sharova2023rareift140associatedphenotype pages 2-4)
Phenotype domain	Skeletal	Congenital; variable severity	Narrow/small thorax or narrow chest, short-rib dysplasia, rhizomelic shortening or small limbs, shortening of long bones, brachydactyly, terminal hypoplasia of fingers, cone-shaped epiphyses, pectus excavatum	Skeletal findings overlap with other ciliopathies and support inclusion in skeletal dysplasia differential diagnosis	HP:0000774 Narrow thorax; HP:0008905 Rhizomelia; HP:0001156 Brachydactyly; HP:0003026 Short rib; HP:0010442 Cone-shaped epiphyses; HP:0000767 Pectus excavatum	(walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 4-5, sharova2023rareift140associatedphenotype pages 2-4)
Phenotype domain	Ectodermal	Early childhood; common and diagnostically useful	Sparse/thin hair, short/thin nails, nail dysplasia, abnormal/small teeth, dental anomalies, skin laxity	Dental and nail findings help distinguish CED from overlapping skeletal ciliopathies	HP:0008070 Sparse hair; HP:0008386 Short nail; HP:0002164 Nail dysplasia; HP:0006482 Abnormality of dental morphology; HP:0001597 Skin laxity	(walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 2-4)
Phenotype domain	Renal	Often progressive in infancy/childhood; major prognostic driver	Nephronophthisis/CKD, chronic renal failure, tubulointerstitial nephritis, early-onset ESRD; ClinicalTrials.gov summary notes many patients develop CKD due to nephronophthisis typically between ages 2–6 years	Severe cases required dialysis, nephrectomy, pediatric kidney transplantation; urinary protein/creatinine ratio 4.32 mg/mmol and urinary microalbumin 595.0 mg/L reported in one 2023 WDR35 case	HP:0000090 Nephronophthisis; HP:0000112 Chronic kidney disease; HP:0003774 Stage 5 chronic kidney disease	(hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 4-6, walczaksztulpa2020compoundheterozygousift140 pages 1-2, NCT04184531 chunk 1, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 4-5, sharova2023rareift140associatedphenotype pages 2-4)
Phenotype domain	Hepatic	Variable; may emerge with progression	Hepatic fibrosis, cystic liver disease, liver anomalies; hepatic and renal disease together broaden CED into a hepatorenal fibrocystic phenotype	Liver involvement is less uniformly described than renal disease but repeatedly noted in case summaries	HP:0001395 Hepatic fibrosis; HP:0001407 Hepatic cysts	(hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Phenotype domain	Ocular	Variable	Retinal dystrophy/retinopathy, hyperopia, strabismus, nystagmus, optic nerve atrophy (reported as common in some IFT140-associated cases, though absent in one 2023 proband)	Ocular involvement is important for longitudinal surveillance because some patients lack eye findings early	HP:0000505 Visual impairment; HP:0000486 Strabismus; HP:0000639 Nystagmus; HP:0000580 Hypermetropia; HP:0000556 Retinal dystrophy	(walczaksztulpa2020compoundheterozygousift140 pages 4-6, NCT04184531 chunk 1, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 1-2)

Table: This table condenses the evidence-supported genetic architecture and major clinical domains of cranioectodermal dysplasia (Sensenbrenner syndrome). It emphasizes the core IFT genes, representative variants, CNV/duplication detection pitfalls, and phenotype domains with example HPO terms for knowledge-base curation.

3.2 Phenotype characteristics: onset, progression, and frequency

Onset: Typically congenital/early childhood features (craniofacial, thoracic, limb, ectodermal). (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 2-4)
Progression: Renal disease is often progressive and may lead to ESRD in infancy/childhood in severe cases (including IFT140-associated CED with dialysis/transplant in the first years of life). (walczaksztulpa2020compoundheterozygousift140 pages 4-6, sharova2023rareift140associatedphenotype pages 4-5, sharova2023rareift140associatedphenotype pages 2-4)
Renal timing (observational trial protocol): The CED observational study protocol notes many patients develop CKD due to nephronophthisis “typically between ages 2–6 years.” (ClinicalTrials.gov NCT04184531; posted 2020; https://clinicaltrials.gov/study/NCT04184531) (NCT04184531 chunk 1)

Quantitative frequency data (e.g., % renal disease, % hepatic fibrosis) were not extractable from the provided text snippets; the major cohort (13 patients/12 families) provides strong qualitative support but not per-feature prevalence in the evidence shown here. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

3.3 Quality-of-life impact

Direct QoL instrument outcomes (e.g., PROMIS, SF-36) were not identified in the retrieved evidence. Functionally, pediatric CKD/ESRD requiring dialysis/transplant and craniosynostosis surgery imply substantial morbidity. (NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)

4. Genetic / molecular information

4.1 Causal genes (current understanding)

An evidence-supported, commonly cited set of six causal genes includes: - IFT122 (IFT-A) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2) - WDR35 (also referred to as IFT121; IFT-A) (gilissen2010exomesequencingidentifies pages 2-3) - IFT140 (IFT-A) (walczaksztulpa2020compoundheterozygousift140 pages 1-2, sharova2023rareift140associatedphenotype pages 1-2) - IFT43 (IFT-related; frequently considered IFT-A-associated) (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3) - WDR19 (IFT-related; IFT-A-associated in cited summaries) (hoffer2013novelwdr35mutations pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2) - IFT52 (IFT-related; included in 6-gene list) (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)

Recent (2023) synthesis in case literature: the 2023 WDR35 case report reiterates the 6-gene framework and notes that “WDR35 variants are one of the most common causes of CED patients.” (Li et al., 2023-08; https://doi.org/10.1186/s12887-023-04110-1) (li2023novelcompoundheterozygous pages 1-3)

Cross-resource confirmation: Open Targets lists strong disease–target associations for IFT122, WDR35, WDR19, IFT43, IFT52, and IFT140 for MONDO_0009032. (OpenTargets Search: Cranioectodermal dysplasia,Sensenbrenner syndrome)

4.2 Pathogenic variant examples (with variant classes)

IFT122 (AJHG 2010): homozygous missense and compound-heterozygous splice-site + missense genotypes in an initial cohort; all reported variants were absent in 340 controls. (Walczak-Sztulpa et al., 2010-06; https://doi.org/10.1016/j.ajhg.2010.04.012) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

WDR35 (AJHG 2010; Clin Genet 2013; BMC Pediatr 2023): - Canonical splice-site + missense and frameshift + missense compound heterozygosity identified by exome sequencing. (Gilissen et al., 2010-09; https://doi.org/10.1016/j.ajhg.2010.08.004) (gilissen2010exomesequencingidentifies pages 2-3) - Examples include splice/frameshift/nonsense/missense alleles; Clin Genet letter provides variants and emphasizes renal/hepatic involvement. (Hoffer et al., 2013-01; https://doi.org/10.1111/j.1399-0004.2012.01880.x) (hoffer2013novelwdr35mutations pages 1-2) - 2023 case report reports novel compound heterozygous variants c.2590C>T (p.Gln864*) (nonsense) and c.2408_2416del (p.Asn803_Ala805del) (in-frame deletion) with a novel phenotype (ectopic testis) in addition to typical CED features. (Li et al., 2023-08; https://doi.org/10.1186/s12887-023-04110-1) (li2023novelcompoundheterozygous pages 1-3)

IFT140 (Orphanet J Rare Dis 2020; Genes 2023): - 2020 report identified compound heterozygosity including a recurrent tandem duplication (exons 27–30 region; protein-level p.Tyr1152_Thr1394dup) plus missense variants; importantly, the duplication “was not detected by NGS analysis,” motivating orthogonal CNV/SV assays (qPCR/duplex PCR/Sanger). (Walczak-Sztulpa et al., 2020-02; https://doi.org/10.1186/s13023-020-1303-2) (walczaksztulpa2020compoundheterozygousift140 pages 4-6) - 2023 report emphasizes diagnostic journey: exome/panel sequencing may detect only one variant; CNV/SV detection (coverage analysis, multiplex PCR) and even WGS may be needed to identify tandem duplications. (Sharova et al., 2023-07; https://doi.org/10.3390/genes14081553) (sharova2023rareift140associatedphenotype pages 1-2, sharova2023rareift140associatedphenotype pages 2-4)

4.3 Somatic vs germline

CED is a germline Mendelian disorder in the cited reports. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3)

4.4 Functional consequences (molecular)

Evidence supports ciliary assembly/maintenance defects, including reduced frequency/length of primary cilia in patient fibroblasts (IFT122), and disrupted IFT-A complex function/ciliary trafficking for WDR35/IFT140. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, caparrosmartin2015specificvariantsin pages 8-9, sharova2023rareift140associatedphenotype pages 2-4)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No definitive modifier genes, epigenetic signatures, or chromosomal abnormality mechanisms were identified in the retrieved evidence snippets for CED specifically.

5. Environmental information

No non-genetic environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence, consistent with a primarily Mendelian ciliopathy. (walczaksztulpa2020compoundheterozygousift140 pages 1-2)

6. Mechanism / pathophysiology

6.1 Key concept: CED as a ciliopathy driven by IFT dysfunction

CED is supported as a ciliopathy by: - Cellular phenotype: reduced frequency/shortened primary cilia in patient fibroblasts with IFT122 mutations. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2) - In vivo functional support: zebrafish ift122 knockdown produces ciliopathy-typical phenotypes. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2) - Ciliary transport gene identification: exome sequencing identifying WDR35 as causal and linking it to IFT-A/retrograde transport biology. (gilissen2010exomesequencingidentifies pages 2-3)

6.2 Upstream-to-downstream causal chain (evidence-based)

1) Biallelic variants in IFT-A/IFT-related genes (e.g., IFT122, WDR35, IFT140) → (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, gilissen2010exomesequencingidentifies pages 2-3, sharova2023rareift140associatedphenotype pages 2-4) 2) Defective ciliogenesis and/or ciliary trafficking (reduced cilia frequency/length; impaired IFT complex assembly/cargo transport) → (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2, caparrosmartin2015specificvariantsin pages 8-9) 3) Dysregulated developmental signaling in cilia, particularly Hedgehog pathway processing/SMO recruitment in WDR35-deficient cell models, consistent with skeletal ciliopathy pathogenesis → (caparrosmartin2015specificvariantsin pages 8-9, caparrosmartin2015specificvariantsin pages 7-8) 4) Tissue-level developmental and homeostatic defects affecting bone/cartilage development (craniosynostosis, narrow thorax, limb shortening) and kidney tubulointerstitial pathology leading to nephronophthisis/CKD/ESRD → (gilissen2010exomesequencingidentifies pages 2-3, NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)

6.3 Molecular pathways implicated

Hedgehog signaling (Hh): Cell-based evidence shows WDR35 perturbation disrupts recruitment of ciliary components and Hedgehog pathway readouts (e.g., GLI processing/SMO enrichment), supporting Hh involvement in skeletal ciliopathy phenotypes. (caparrosmartin2015specificvariantsin pages 8-9, caparrosmartin2015specificvariantsin pages 7-8)

6.4 Suggested ontology terms

GO biological processes / complexes:
GO:0030990 (intraflagellar transport particle A) (supported by IFT-A gene involvement in evidence) (gilissen2010exomesequencingidentifies pages 2-3, walczaksztulpa2020compoundheterozygousift140 pages 1-2)
GO:0005929 (cilium) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)
Cell Ontology (CL; plausible major involved cell types, not directly assayed in retrieved evidence): renal tubular epithelial cell (CL:0000064) and osteoblast/chondrocyte lineages are biologically plausible but not directly evidenced in the provided excerpts.

6.5 Molecular profiling and advanced technologies

A key recent practical development (2023) is the explicit incorporation of WGS and SV calling to resolve missing second alleles (e.g., tandem duplication) after panel/WES detects only one IFT140 variant. (sharova2023rareift140associatedphenotype pages 1-2, sharova2023rareift140associatedphenotype pages 2-4)

7. Anatomical structures affected

7.1 Organ level (UBERON suggestions)

Kidney (UBERON:0002113): nephronophthisis/CKD/ESRD; dialysis/transplant in severe cases. (NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)
Liver (UBERON:0002107): hepatic fibrosis/cystic liver disease in some patients. (hoffer2013novelwdr35mutations pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Skeleton (UBERON:0000982) including thorax/ribs and limbs: narrow thorax/short ribs/limb shortening. (gilissen2010exomesequencingidentifies pages 2-3, li2023novelcompoundheterozygous pages 1-3)
Cranium (UBERON:0003129): craniosynostosis/dolichocephaly; craniofacial dysmorphism. (NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)

7.2 Tissue/cell level and subcellular localization

Subcellular: primary cilium (GO:0005929) is central. (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

8. Temporal development

Typical onset: congenital/infantile signs (craniofacial and skeletal); ectodermal anomalies often noted in childhood. (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3)
Renal progression: may present as CKD in early childhood (protocol suggests ages ~2–6 years) or can be severe in infancy with IFT140-associated cases requiring dialysis/transplant within the first 2 years. (NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)

9. Inheritance and population

9.1 Inheritance

Autosomal recessive inheritance is consistently stated across gene-discovery and case literature. (gilissen2010exomesequencingidentifies pages 1-2, walczaksztulpa2020compoundheterozygousift140 pages 1-2, sharova2023rareift140associatedphenotype pages 1-2)

9.2 Epidemiology

Prevalence/incidence estimates were not available in the retrieved evidence excerpts. CED is repeatedly described as rare/ultra-rare in the cited literature. (walczaksztulpa2020compoundheterozygousift140 pages 1-2)

10. Diagnostics

10.1 Clinical and imaging evaluation

Recognition of a craniofacial–skeletal–ectodermal pattern (craniosynostosis/dolichocephaly; narrow thorax/short limbs; hair/nail/teeth anomalies) supports clinical suspicion. (walczaksztulpa2020compoundheterozygousift140 pages 1-2, li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 2-4)

10.2 Genetic testing (current best practice reflected in recent literature)

WES/panel sequencing is highly useful, but structural variant detection may be essential: - Exome sequencing successfully identified WDR35 compound heterozygous variants in two unrelated cases and demonstrated strong diagnostic value for genetically heterogeneous ciliopathies. (Gilissen et al., 2010-09; https://doi.org/10.1016/j.ajhg.2010.08.004) (gilissen2010exomesequencingidentifies pages 2-3) - A major recent diagnostic lesson is that multi-exon tandem duplications (e.g., IFT140 exons 27–30/31) can be missed by standard NGS variant calling and require coverage-based CNV detection and orthogonal validation (multiplex PCR/qPCR/duplex PCR/Sanger); WGS may be needed when only a single allele is initially found. (walczaksztulpa2020compoundheterozygousift140 pages 4-6, sharova2023rareift140associatedphenotype pages 2-4)

Visual evidence (Table/Figure extract): Sharova et al. provide a comparative table of IFT140-associated cranioectodermal phenotype cases and a figure summarizing IFT140 variant distribution, supporting the multi-variant and SV-aware diagnostic approach. (sharova2023rareift140associatedphenotype media c08d3b9a, sharova2023rareift140associatedphenotype media bc07c0ea)

10.3 Differential diagnosis (overlap disorders)

CED overlaps clinically and genetically with other skeletal ciliopathies (e.g., short-rib thoracic dysplasia and Mainzer–Saldino syndrome) particularly through shared IFT gene involvement (e.g., IFT140 more commonly Mainzer–Saldino but can present with cranioectodermal phenotype). (sharova2023rareift140associatedphenotype pages 1-2)

11. Outcome / prognosis

11.1 Key prognostic drivers

Kidney and liver involvement are repeatedly emphasized as primary determinants of prognosis. - Direct quote (2023): the 2023 WDR35 report states that “liver and kidney function are the main factors determining the CED prognosis.” (Li et al., 2023-08; https://doi.org/10.1186/s12887-023-04110-1) (li2023novelcompoundheterozygous pages 1-3) - Severe early-onset renal disease requiring transplant is reported in IFT140-associated cases. (walczaksztulpa2020compoundheterozygousift140 pages 4-6, sharova2023rareift140associatedphenotype pages 2-4)

11.2 Morbidity

Pediatric CKD/ESRD (dialysis/transplant) and craniosynostosis surgery indicate high morbidity and complex multidisciplinary care needs. (NCT04184531 chunk 1, sharova2023rareift140associatedphenotype pages 2-4)

Survival/life expectancy statistics were not available in the retrieved evidence.

12. Treatment

12.1 Disease-modifying therapy

No disease-modifying therapy was identified in the retrieved evidence excerpts; management is primarily supportive and complication-directed.

12.2 Supportive / real-world management examples

In the 2023 WDR35 case report, supportive management included iron succinate and erythropoietin for anemia and measures addressing metabolic acidosis/hyperkalemia, while renal replacement therapy was declined by the family. (Li et al., 2023-08; https://doi.org/10.1186/s12887-023-04110-1) (li2023novelcompoundheterozygous pages 1-3)
Renal replacement therapy (dialysis/transplantation) is a real-world intervention for severe disease, including IFT140-related cases. (walczaksztulpa2020compoundheterozygousift140 pages 4-6, sharova2023rareift140associatedphenotype pages 2-4)

12.3 MAXO suggestions (for knowledge base annotation; evidence-informed)

Kidney transplantation (MAXO:0001175) (supported by pediatric transplant reports) (walczaksztulpa2020compoundheterozygousift140 pages 4-6, sharova2023rareift140associatedphenotype pages 2-4)
Dialysis (MAXO:0000601) (sharova2023rareift140associatedphenotype pages 2-4)
Genetic counseling (MAXO:0000079) (supported by multiple sources emphasizing counseling/diagnostic path) (li2023novelcompoundheterozygous pages 1-3, sharova2023rareift140associatedphenotype pages 1-2)

12.4 Clinical trials

An observational study specifically targeting CED/Sensenbrenner syndrome was registered: - NCT04184531 (Sensenbrenner Clinical Study), retrospective cohort; estimated enrollment 4; aims include craniofacial characterization and possible prognostic factors for CKD. (ClinicalTrials.gov; posted 2020; https://clinicaltrials.gov/study/NCT04184531) (NCT04184531 chunk 1)

13. Prevention

Because CED is autosomal recessive, prevention is primarily via genetic counseling and reproductive options rather than environmental modification. - The 2023 WDR35 case report explicitly frames its contribution as providing “genetic counseling for prevention and intervention in this genetic disorder,” and advocates follow-up for carriers. (Li et al., 2023-08; https://doi.org/10.1186/s12887-023-04110-1) (li2023novelcompoundheterozygous pages 1-3)

14. Other species / natural disease

No naturally occurring veterinary CED analogue was identified in the retrieved evidence.

15. Model organisms

15.1 Zebrafish

Transient knockdown of ift122 in zebrafish embryos produced a phenotype described as typical of ciliopathy models, supporting conserved developmental roles for IFT122. (Walczak-Sztulpa et al., 2010-06; https://doi.org/10.1016/j.ajhg.2010.04.012) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)

15.2 Mouse / cell models informing skeletal ciliopathy mechanisms

While not always labeled as CED models per se, multiple IFT-A pathway models are mechanistically relevant: - WDR35/Wdr35: Human and mouse mutations cause severe skeletal ciliopathy phenotypes due to abnormal ciliogenesis; mouse mutant shows defects characteristic of impaired Hedgehog signaling; fibroblasts lacking WDR35 fail to form cilia. (Mill et al., 2011-04; https://doi.org/10.1016/j.ajhg.2011.03.015) (mill2011humanandmouse pages 1-3) - Wdr35 functional cell evidence (Hedgehog/ciliary recruitment): Wdr35−/− MEFs demonstrate altered Hedgehog pathway readouts and disrupted ciliary localization of components including IFT43, with effects on SMO/EvC complex recruitment. (Caparrós-Martín et al., 2015-04; https://doi.org/10.1093/hmg/ddv152) (caparrosmartin2015specificvariantsin pages 8-9, caparrosmartin2015specificvariantsin pages 7-8)

Recent developments (prioritized 2023–2024)

1) Expanded and more granular genotype–phenotype reporting: a 2023 WDR35 case adds novel alleles and a novel associated feature (ectopic testis) while reiterating renal/hepatic prognosis determinants. (li2023novelcompoundheterozygous pages 1-3) 2) Improved diagnostic workflows emphasizing SV/CNV and WGS: 2023 IFT140-CED report provides a detailed “diagnostic journey,” demonstrating that tandem duplications can be missed by panel/WES and may require WGS and targeted assays. (sharova2023rareift140associatedphenotype pages 1-2, sharova2023rareift140associatedphenotype pages 2-4)

Key statistics and data points (from retrieved studies)

IFT122 AJHG cohort size: 13 patients from 12 families studied in the landmark IFT122 gene-discovery work. (Walczak-Sztulpa et al., 2010-06) (walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2)
Genetic heterogeneity: A 2020 synthesis cites six associated genes (IFT122, WDR35, IFT140, IFT43, IFT52, WDR19). (walczaksztulpa2020compoundheterozygousift140 pages 1-2)
IFT140-cranioectodermal phenotype rarity (2023): “Only four patients have previously been described” (Sharova et al., 2023-07). (sharova2023rareift140associatedphenotype pages 1-2)
Clinical trial enrollment (observational): NCT04184531 estimated enrollment n=4. (NCT04184531 chunk 1)

Limitations of this report (evidence availability)

The current tool-retrieved corpus did not provide Orphanet/ICD/MeSH identifiers, prevalence/incidence estimates, or standardized diagnostic criteria documents. Where not supported by the retrieved evidence snippets, the report explicitly marks information as unavailable rather than inferring.

References

(walczaksztulpa2010cranioectodermaldysplasiasensenbrenner pages 1-2): Joanna Walczak-Sztulpa, Jonathan Eggenschwiler, Daniel Osborn, Desmond A. Brown, Francesco Emma, Claus Klingenberg, Raoul C. Hennekam, Giuliano Torre, Masoud Garshasbi, Andreas Tzschach, Malgorzata Szczepanska, Marian Krawczynski, Jacek Zachwieja, Danuta Zwolinska, Philip L. Beales, Hans-Hilger Ropers, Anna Latos-Bielenska, and Andreas W. Kuss. Cranioectodermal dysplasia, sensenbrenner syndrome, is a ciliopathy caused by mutations in the ift122 gene. American journal of human genetics, 86 6:949-56, Jun 2010. URL: https://doi.org/10.1016/j.ajhg.2010.04.012, doi:10.1016/j.ajhg.2010.04.012. This article has 242 citations and is from a highest quality peer-reviewed journal.
(gilissen2010exomesequencingidentifies pages 2-3): Christian Gilissen, Heleen H. Arts, Alexander Hoischen, Liesbeth Spruijt, Dorus A. Mans, Peer Arts, Bart van Lier, Marloes Steehouwer, Jeroen van Reeuwijk, Sarina G. Kant, Ronald Roepman, Nine V.A.M. Knoers, Joris A. Veltman, and Han G. Brunner. Exome sequencing identifies wdr35 variants involved in sensenbrenner syndrome. American journal of human genetics, 87 3:418-23, Sep 2010. URL: https://doi.org/10.1016/j.ajhg.2010.08.004, doi:10.1016/j.ajhg.2010.08.004. This article has 360 citations and is from a highest quality peer-reviewed journal.
(walczaksztulpa2020compoundheterozygousift140 pages 1-2): Joanna Walczak-Sztulpa, Renata Posmyk, Ewelina M. Bukowska-Olech, Anna Wawrocka, Aleksander Jamsheer, Machteld M. Oud, Miriam Schmidts, Heleen H. Arts, Anna Latos-Bielenska, and Anna Wasilewska. Compound heterozygous ift140 variants in two polish families with sensenbrenner syndrome and early onset end-stage renal disease. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1303-2, doi:10.1186/s13023-020-1303-2. This article has 26 citations and is from a peer-reviewed journal.
(li2023novelcompoundheterozygous pages 1-3): Lijie Li, Cuihua Liu, Ming Tian, Guangbo Li, and Jitong Li. Novel compound heterozygous wdr35 variants in a chinese patient associated with cranioectodermal dysplasia and ectopic testis: a case report and review of the literature. BMC Pediatrics, Aug 2023. URL: https://doi.org/10.1186/s12887-023-04110-1, doi:10.1186/s12887-023-04110-1. This article has 1 citations and is from a peer-reviewed journal.
(gilissen2010exomesequencingidentifies pages 1-2): Christian Gilissen, Heleen H. Arts, Alexander Hoischen, Liesbeth Spruijt, Dorus A. Mans, Peer Arts, Bart van Lier, Marloes Steehouwer, Jeroen van Reeuwijk, Sarina G. Kant, Ronald Roepman, Nine V.A.M. Knoers, Joris A. Veltman, and Han G. Brunner. Exome sequencing identifies wdr35 variants involved in sensenbrenner syndrome. American journal of human genetics, 87 3:418-23, Sep 2010. URL: https://doi.org/10.1016/j.ajhg.2010.08.004, doi:10.1016/j.ajhg.2010.08.004. This article has 360 citations and is from a highest quality peer-reviewed journal.
(hoffer2013novelwdr35mutations pages 1-2): JL Hoffer, H. Fryssira, A. Konstantinidou, H. Ropers, A. Tzschach, and A. Tzschach. Novel wdr35 mutations in patients with cranioectodermal dysplasia (sensenbrenner syndrome). Clinical Genetics, 83:92-95, Jan 2013. URL: https://doi.org/10.1111/j.1399-0004.2012.01880.x, doi:10.1111/j.1399-0004.2012.01880.x. This article has 43 citations and is from a peer-reviewed journal.
(NCT04184531 chunk 1): Sensenbrenner Clinical Study. Hospices Civils de Lyon. 2020. ClinicalTrials.gov Identifier: NCT04184531
(OpenTargets Search: Cranioectodermal dysplasia,Sensenbrenner syndrome): Open Targets Query (Cranioectodermal dysplasia,Sensenbrenner syndrome, 20 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(sharova2023rareift140associatedphenotype pages 1-2): Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, and Sergey Kutsev. Rare ift140-associated phenotype of cranioectodermal dysplasia and features of diagnostic journey in patients with suspected ciliopathies. Genes, 14:1553, Jul 2023. URL: https://doi.org/10.3390/genes14081553, doi:10.3390/genes14081553. This article has 6 citations.
(walczaksztulpa2020compoundheterozygousift140 pages 4-6): Joanna Walczak-Sztulpa, Renata Posmyk, Ewelina M. Bukowska-Olech, Anna Wawrocka, Aleksander Jamsheer, Machteld M. Oud, Miriam Schmidts, Heleen H. Arts, Anna Latos-Bielenska, and Anna Wasilewska. Compound heterozygous ift140 variants in two polish families with sensenbrenner syndrome and early onset end-stage renal disease. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1303-2, doi:10.1186/s13023-020-1303-2. This article has 26 citations and is from a peer-reviewed journal.
(sharova2023rareift140associatedphenotype pages 4-5): Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, and Sergey Kutsev. Rare ift140-associated phenotype of cranioectodermal dysplasia and features of diagnostic journey in patients with suspected ciliopathies. Genes, 14:1553, Jul 2023. URL: https://doi.org/10.3390/genes14081553, doi:10.3390/genes14081553. This article has 6 citations.
(sharova2023rareift140associatedphenotype pages 2-4): Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, and Sergey Kutsev. Rare ift140-associated phenotype of cranioectodermal dysplasia and features of diagnostic journey in patients with suspected ciliopathies. Genes, 14:1553, Jul 2023. URL: https://doi.org/10.3390/genes14081553, doi:10.3390/genes14081553. This article has 6 citations.
(caparrosmartin2015specificvariantsin pages 8-9): José A. Caparrós-Martín, Alessandro De Luca, François Cartault, Mona Aglan, Samia Temtamy, Ghada A. Otaify, Mennat Mehrez, María Valencia, Laura Vázquez, Jean-Luc Alessandri, Julián Nevado, Inmaculada Rueda-Arenas, Karen E. Heath, Maria Cristina Digilio, Bruno Dallapiccola, Judith A. Goodship, Pleasantine Mill, Pablo Lapunzina, and Victor L. Ruiz-Perez. 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. Human molecular genetics, 24 14:4126-37, Apr 2015. URL: https://doi.org/10.1093/hmg/ddv152, doi:10.1093/hmg/ddv152. This article has 74 citations and is from a domain leading peer-reviewed journal.
(caparrosmartin2015specificvariantsin pages 7-8): José A. Caparrós-Martín, Alessandro De Luca, François Cartault, Mona Aglan, Samia Temtamy, Ghada A. Otaify, Mennat Mehrez, María Valencia, Laura Vázquez, Jean-Luc Alessandri, Julián Nevado, Inmaculada Rueda-Arenas, Karen E. Heath, Maria Cristina Digilio, Bruno Dallapiccola, Judith A. Goodship, Pleasantine Mill, Pablo Lapunzina, and Victor L. Ruiz-Perez. 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. Human molecular genetics, 24 14:4126-37, Apr 2015. URL: https://doi.org/10.1093/hmg/ddv152, doi:10.1093/hmg/ddv152. This article has 74 citations and is from a domain leading peer-reviewed journal.
(sharova2023rareift140associatedphenotype media c08d3b9a): Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, and Sergey Kutsev. Rare ift140-associated phenotype of cranioectodermal dysplasia and features of diagnostic journey in patients with suspected ciliopathies. Genes, 14:1553, Jul 2023. URL: https://doi.org/10.3390/genes14081553, doi:10.3390/genes14081553. This article has 6 citations.
(sharova2023rareift140associatedphenotype media bc07c0ea): Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, and Sergey Kutsev. Rare ift140-associated phenotype of cranioectodermal dysplasia and features of diagnostic journey in patients with suspected ciliopathies. Genes, 14:1553, Jul 2023. URL: https://doi.org/10.3390/genes14081553, doi:10.3390/genes14081553. This article has 6 citations.
(mill2011humanandmouse pages 1-3): Pleasantine Mill, Paul J. Lockhart, Elizabeth Fitzpatrick, Hayley S. Mountford, Emma A. Hall, Martin A.M. Reijns, Margaret Keighren, Melanie Bahlo, Catherine J. Bromhead, Peter Budd, Salim Aftimos, Martin B. Delatycki, Ravi Savarirayan, Ian J. Jackson, and David J. Amor. Human and mouse mutations in wdr35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. American journal of human genetics, 88 4:508-15, Apr 2011. URL: https://doi.org/10.1016/j.ajhg.2011.03.015, doi:10.1016/j.ajhg.2011.03.015. This article has 160 citations and is from a highest quality peer-reviewed journal.

Artifacts

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OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Cranioectodermal Dysplasia (CED) / Sensenbrenner syndrome

Executive summary

1. Disease information

1.1 Overview / definition (current understanding)

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence type note

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core phenotype domains and HPO suggestions

3.2 Phenotype characteristics: onset, progression, and frequency

3.3 Quality-of-life impact

4. Genetic / molecular information

4.1 Causal genes (current understanding)

4.2 Pathogenic variant examples (with variant classes)

4.3 Somatic vs germline

4.4 Functional consequences (molecular)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Key concept: CED as a ciliopathy driven by IFT dysfunction

6.2 Upstream-to-downstream causal chain (evidence-based)

6.3 Molecular pathways implicated

6.4 Suggested ontology terms

6.5 Molecular profiling and advanced technologies

7. Anatomical structures affected

7.1 Organ level (UBERON suggestions)

7.2 Tissue/cell level and subcellular localization

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology

10. Diagnostics

10.1 Clinical and imaging evaluation

10.2 Genetic testing (current best practice reflected in recent literature)

10.3 Differential diagnosis (overlap disorders)

11. Outcome / prognosis

11.1 Key prognostic drivers

11.2 Morbidity

12. Treatment

12.1 Disease-modifying therapy

12.2 Supportive / real-world management examples

12.3 MAXO suggestions (for knowledge base annotation; evidence-informed)

12.4 Clinical trials