Cranioectodermal dysplasia

Summary

Cranioectodermal dysplasia (MONDO:0009032) is a disease (an umbrella term covering 7 Mondo subtypes) with 7 cohort genes and 3 clinical trials. The dominant Reactome pathway is Intraflagellar transport (6 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 10
• Phenotypes (HPO): 30
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0008905	Rhizomelia	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000268	Dolichocephaly	Very frequent (80-99%)
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000691	Microdontia	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0000940	Abnormal diaphysis morphology	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0008388	Abnormal toenail morphology	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000601	Hypotelorism	Frequent (30-79%)
HP:0000668	Hypodontia	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001363	Craniosynostosis	Frequent (30-79%)
HP:0006101	Finger syndactyly	Frequent (30-79%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000679	Taurodontia	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0008499	High hypermetropia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cranioectodermal dysplasia
Mondo ID	MONDO:0009032
OMIM	218330
Orphanet	1515
DOID	DOID:0050577
ICD-11	1588881145
NCIT	C129305
SNOMED CT	254093009
UMLS	C4551571
MedGen	1641011
GARD	0000359
Is cancer (heuristic)	no

Also known as: CED · cranioectodermal dysplasia · Sensenbrenner syndrome

Data availability: 10 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › craniosynostosis syndrome, autosomal recessive › cranioectodermal dysplasia

Related subtypes (1): Antley-Bixler syndrome

Subtypes (7): cranioectodermal dysplasia 2, cranioectodermal dysplasia 3, cranioectodermal dysplasia 4, short-rib thoracic dysplasia 16 with or without polydactyly, cranioectodermal dysplasia 1, cranioectodermal dysplasia 5, cranioectodermal dysplasia 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

10 retrieved; paginated sample, class counts are floors:

5 pathogenic, 3 pathogenic/likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3366972	NM_014920.5(CILK1):c.1664_1665del (p.Tyr555fs)	CILK1	Pathogenic	criteria provided, single submitter
191185	NM_052989.3(IFT122):c.2375+2T>C	IFT122	Pathogenic	criteria provided, single submitter
523177	NM_014714.4(IFT140):c.3454-488_4182+2588dup	IFT140	Pathogenic	criteria provided, single submitter
523181	NM_014714.4(IFT140):c.2177C>T (p.Pro726Leu)	IFT140	Pathogenic	criteria provided, single submitter
127158	NM_025132.4(WDR19):c.3533G>A (p.Arg1178Gln)	WDR19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
266105	NM_025132.4(WDR19):c.1434C>G (p.Ile478Met)	WDR19	Pathogenic/Likely pathogenic	no assertion criteria provided
558759	NM_025132.4(WDR19):c.1623C>G (p.Tyr541Ter)	WDR19	Pathogenic	criteria provided, multiple submitters, no conflicts
65619	NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819099	NM_052989.3(IFT122):c.1637A>C (p.Lys546Thr)	IFT122	Uncertain significance	criteria provided, single submitter
65741	NM_052989.3(IFT122):c.1483G>A (p.Gly495Arg)	IFT122	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IFT122	Definitive	Autosomal recessive	cranioectodermal dysplasia 1	4
WDR19	Definitive	Autosomal recessive	cranioectodermal dysplasia 4	12
WDR35	Definitive	Autosomal recessive	cranioectodermal dysplasia 2	8
IFT43	Strong	Autosomal recessive	short-rib thoracic dysplasia 18 with polydactyly	10
IFT52	Strong	Autosomal recessive	short-rib thoracic dysplasia 16 with or without polydactyly	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFT122	Orphanet:1515	Cranioectodermal dysplasia
IFT122	Orphanet:93268	Short rib-polydactyly syndrome, Beemer-Langer type
WDR19	Orphanet:1515	Cranioectodermal dysplasia
WDR19	Orphanet:3156	Senior-Loken syndrome
WDR19	Orphanet:474	Jeune syndrome
WDR19	Orphanet:93592	Juvenile nephronophthisis
WDR35	Orphanet:1515	Cranioectodermal dysplasia
WDR35	Orphanet:498497	Short rib-polydactyly syndrome type 5
WDR35	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
IFT52	Orphanet:1515	Cranioectodermal dysplasia
IFT43	Orphanet:1515	Cranioectodermal dysplasia
IFT43	Orphanet:791	Retinitis pigmentosa
CILK1	Orphanet:199332	Endocrine-cerebro-osteodysplasia syndrome
CILK1	Orphanet:307	Juvenile myoclonic epilepsy
IFT140	Orphanet:140969	Saldino-Mainzer syndrome
IFT140	Orphanet:474	Jeune syndrome
IFT140	Orphanet:65	Leber congenital amaurosis
IFT140	Orphanet:730	Autosomal dominant polycystic kidney disease
IFT140	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IFT122	HGNC:13556	ENSG00000163913	Q9HBG6	Intraflagellar transport protein 122 homolog	gencc,clinvar
WDR19	HGNC:18340	ENSG00000157796	Q8NEZ3	WD repeat-containing protein 19	gencc,clinvar
WDR35	HGNC:29250	ENSG00000118965	Q9P2L0	WD repeat-containing protein 35	gencc,clinvar
IFT52	HGNC:15901	ENSG00000101052	Q9Y366	Intraflagellar transport protein 52 homolog	gencc
IFT43	HGNC:29669	ENSG00000119650	Q96FT9	Intraflagellar transport protein 43 homolog	gencc
CILK1	HGNC:21219	ENSG00000112144	Q9UPZ9	Serine/threonine-protein kinase ICK	clinvar
IFT140	HGNC:29077	ENSG00000187535	Q96RY7	Intraflagellar transport protein 140 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFT122	Intraflagellar transport protein 122 homolog	As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is required in ciliogenesis and ciliary protein trafficking.
WDR19	WD repeat-containing protein 19	As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly.
WDR35	WD repeat-containing protein 35	As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in ciliogenesis and ciliary protein trafficking.
IFT52	Intraflagellar transport protein 52 homolog	Involved in ciliogenesis as part of a complex involved in intraflagellar transport (IFT), the bi-directional movement of particles required for the assembly, maintenance and functioning of primary cilia.
IFT43	Intraflagellar transport protein 43 homolog	As a component of IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in ciliogenesis.
CILK1	Serine/threonine-protein kinase ICK	Required for ciliogenesis.
IFT140	Intraflagellar transport protein 140 homolog	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).

Protein-family classification

Druggable: 1 · Difficult: 4 · Unknown: 2 · Druggable fraction: 0.14

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	2	4.9×	0.231
Kinase	1	4.0×	0.302
Transcription factor	2	2.4×	0.302
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFT122	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
WDR19	Transcription factor	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
WDR35	Transcription factor	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WDR35
IFT52	Other/Unknown	no		IFT52, Itf52_C, IFT52_GIFT
IFT43	Other/Unknown	no		IFT43
CILK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
IFT140	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	4
bronchial epithelial cell	3
bronchus	2
cortical plate	2
left testis	1
right testis	1
adenohypophysis	1
mucosa of paranasal sinus	1
ganglionic eminence	1
ventricular zone	1
adrenal tissue	1
palpebral conjunctiva	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFT122	250	ubiquitous	marker	right testis, left testis, right uterine tube
WDR19	269	ubiquitous	marker	right uterine tube, bronchial epithelial cell, adenohypophysis
WDR35	257	ubiquitous	marker	bronchial epithelial cell, mucosa of paranasal sinus, bronchus
IFT52	254	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
IFT43	252	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
CILK1	268	ubiquitous	marker	adrenal tissue, palpebral conjunctiva, cortical plate
IFT140	214	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFT122	2,519
IFT140	1,602
CILK1	1,317
IFT52	1,254
WDR19	1,251
WDR35	1,032
IFT43	635

Intra-cohort edges

A	B	Sources
CILK1	WDR19	string_interaction
IFT122	IFT140	biogrid_interaction, intact, string_interaction
IFT122	IFT43	biogrid_interaction, intact, string_interaction
IFT122	IFT52	string_interaction
IFT122	WDR19	biogrid_interaction, intact, string_interaction
IFT122	WDR35	biogrid_interaction, intact, string_interaction
IFT140	IFT43	biogrid_interaction, intact, string_interaction
IFT140	IFT52	string_interaction
IFT140	WDR19	biogrid_interaction, intact, string_interaction
IFT140	WDR35	biogrid_interaction, intact, string_interaction
IFT43	IFT52	string_interaction
IFT43	WDR19	biogrid_interaction, intact, string_interaction
IFT43	WDR35	biogrid_interaction, intact, string_interaction
IFT52	WDR19	string_interaction
IFT52	WDR35	string_interaction
WDR19	WDR35	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IFT122	Q9HBG6	5
WDR19	Q8NEZ3	4
WDR35	Q9P2L0	4
IFT140	Q96RY7	4
IFT43	Q96FT9	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT52	Q9Y366	84.21
CILK1	Q9UPZ9	61.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 7 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	6	200.3×	2e-14	IFT122, WDR19, WDR35, IFT52, IFT140, IFT43
Hedgehog ‘off’ state	5	148.7×	3e-11	IFT122, WDR19, WDR35, IFT52, IFT140

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intraciliary retrograde transport	6	963.0×	5e-17	IFT122, WDR19, WDR35, CILK1, IFT140, IFT43
cilium assembly	7	73.6×	2e-12	IFT122, WDR19, WDR35, IFT52, CILK1, IFT140, IFT43
intraciliary transport	4	321.0×	5e-09	IFT122, WDR35, IFT52, CILK1
intraciliary anterograde transport	3	380.1×	5e-07	IFT122, IFT52, CILK1
protein localization to cilium	3	172.0×	5e-06	IFT122, WDR35, IFT140
non-motile cilium assembly	3	124.5×	1e-05	IFT122, IFT52, IFT140
embryonic camera-type eye development	2	343.9×	9e-05	WDR19, IFT140
embryonic cranial skeleton morphogenesis	2	166.0×	4e-04	WDR19, IFT140
embryonic digit morphogenesis	2	86.0×	0.001	IFT52, IFT140
ear morphogenesis	1	601.9×	0.007	WDR19
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	601.9×	0.007	WDR19
myotome development	1	601.9×	0.007	WDR19
digestive system development	1	481.5×	0.007	WDR19
protein localization to ciliary membrane	1	481.5×	0.007	WDR19
neural tube patterning	1	401.2×	0.008	IFT140
embryonic heart tube left/right pattern formation	1	401.2×	0.008	IFT122
neural tube formation	1	300.9×	0.009	IFT52
embryonic body morphogenesis	1	300.9×	0.009	IFT122
spinal cord dorsal/ventral patterning	1	300.9×	0.009	IFT122
establishment of protein localization to organelle	1	267.5×	0.009	IFT122
regulation of protein processing	1	218.9×	0.011	IFT52
nervous system process	1	172.0×	0.013	WDR19
gonad development	1	160.5×	0.013	WDR19
photoreceptor cell outer segment organization	1	150.5×	0.014	IFT140
embryonic brain development	1	114.6×	0.017	IFT140
embryonic heart tube development	1	109.4×	0.017	IFT122
camera-type eye morphogenesis	1	109.4×	0.017	IFT122
negative regulation of keratinocyte proliferation	1	100.3×	0.017	IFT52
regulation of smoothened signaling pathway	1	89.2×	0.018	IFT140
receptor clustering	1	89.2×	0.018	WDR19

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 1 of 7 evidence-associated genes (14%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CILK1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CILK1	24	4
IFT122	0	0
WDR19	0	0
WDR35	0	0
IFT52	0	0
IFT43	0	0
IFT140	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	CILK1
FEDRATINIB	4	CILK1
PACRITINIB	4	CILK1
ABEMACICLIB	4	CILK1
NINTEDANIB	4	CILK1
SUNITINIB	4	CILK1
MIDOSTAURIN	4	CILK1
DINACICLIB	3	CILK1
ENZASTAURIN	3	CILK1
ALVOCIDIB	3	CILK1
LESTAURTINIB	3	CILK1
RUBOXISTAURIN	3	CILK1
SILMITASERTIB	2	CILK1
SU-014813	2	CILK1
RG-547	2	CILK1
AT-7519	2	CILK1
PICTILISIB	2	CILK1
MILCICLIB	2	CILK1
SOTRASTAURIN	2	CILK1
KW-2449	1	CILK1
BMS-387032	1	CILK1
PF-03758309	1	CILK1
RGB-286638	1	CILK1
AST-487	1	CILK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CILK1	119	Binding:119

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CILK1	119

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

24 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	CILK1
FEDRATINIB	4	CILK1
PACRITINIB	4	CILK1
ABEMACICLIB	4	CILK1
NINTEDANIB	4	CILK1
SUNITINIB	4	CILK1
MIDOSTAURIN	4	CILK1
DINACICLIB	3	CILK1
ENZASTAURIN	3	CILK1
ALVOCIDIB	3	CILK1
LESTAURTINIB	3	CILK1
RUBOXISTAURIN	3	CILK1
SILMITASERTIB	2	CILK1
SU-014813	2	CILK1
RG-547	2	CILK1
AT-7519	2	CILK1
PICTILISIB	2	CILK1
MILCICLIB	2	CILK1
SOTRASTAURIN	2	CILK1
KW-2449	1	CILK1
BMS-387032	1	CILK1
PF-03758309	1	CILK1
RGB-286638	1	CILK1
AST-487	1	CILK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CILK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	IFT122, WDR19, WDR35, IFT52, IFT43, IFT140

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IFT122	0	—
WDR19	0	—
WDR35	0	—
IFT52	0	—
IFT43	0	—
IFT140	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06626282	Not specified	RECRUITING	Fertility and Ovarian Reserve in Female Childhood Cancer Survivors
NCT04032756	Not specified	TERMINATED	Tofacitinib Registry of Patients With Ulcerative Colitis in Germany
NCT04184531	Not specified	UNKNOWN	Sensenbrenner Clinical Study