Cranioectodermal dysplasia 2

Summary

Cranioectodermal dysplasia 2 (MONDO:0013323) is a disease caused by WDR35 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: WDR35 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 669

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cranioectodermal dysplasia 2
Mondo ID	MONDO:0013323
OMIM	613610
DOID	DOID:0080804
UMLS	C3150874
MedGen	462224
GARD	0015680
Is cancer (heuristic)	no

Also known as: CED2 · cranioectodermal dysplasia 2 · cranioectodermal dysplasia caused by mutation in WDR35 · Cranioectodermal dysplasia type 2 · WDR35 cranioectodermal dysplasia · WDR35-related cranioectodermal dysplasia

Data availability: 669 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › cranioectodermal dysplasia 2

Related subtypes (6): 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

600 retrieved; paginated sample, class counts are floors:

278 uncertain significance, 173 likely benign, 45 conflicting classifications of pathogenicity, 32 benign, 28 pathogenic, 23 likely pathogenic, 12 benign/likely benign, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072199	NM_020779.4(WDR35):c.2638dup (p.Thr880fs)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075625	NM_020779.4(WDR35):c.1690C>T (p.Arg564Ter)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1360910	NM_020779.4(WDR35):c.1954_1955insAAAC (p.Leu652fs)	WDR35	Pathogenic	criteria provided, single submitter
1368965	NM_020779.4(WDR35):c.1694_1695dup (p.Thr566Ter)	WDR35	Pathogenic	criteria provided, single submitter
1415290	NM_020779.4(WDR35):c.297del (p.Met99fs)	WDR35	Pathogenic	criteria provided, single submitter
1435158	NM_020779.4(WDR35):c.136C>T (p.Gln46Ter)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459665	NC_000002.11:g.(?20153575)(20153759_?)del	WDR35	Pathogenic	criteria provided, single submitter
1978470	NM_020779.4(WDR35):c.2701G>T (p.Glu901Ter)	WDR35	Pathogenic	criteria provided, single submitter
20	NM_020779.4(WDR35):c.25-2A>G	WDR35	Pathogenic	no assertion criteria provided
21	NM_020779.4(WDR35):c.1844A>G (p.Glu615Gly)	WDR35	Pathogenic	no assertion criteria provided
22	NM_020779.4(WDR35):c.2858del (p.Pro953fs)	WDR35	Pathogenic	criteria provided, single submitter
2423459	NC_000002.11:g.(?20188906)(20189063_?)del	WDR35	Pathogenic	criteria provided, single submitter
2631751	NM_020779.4(WDR35):c.524del (p.Met175fs)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286673	NM_020779.4(WDR35):c.1255+1G>A	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
289210	NM_020779.4(WDR35):c.1468del (p.Gln490fs)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2939861	NM_020779.4(WDR35):c.1554C>G (p.Tyr518Ter)	WDR35	Pathogenic	criteria provided, single submitter
2948787	NM_020779.4(WDR35):c.1322G>A (p.Trp441Ter)	WDR35	Pathogenic	criteria provided, single submitter
2951856	NM_020779.4(WDR35):c.1609C>T (p.Gln537Ter)	WDR35	Pathogenic	criteria provided, single submitter
2952744	NM_020779.4(WDR35):c.171_178del (p.Ser59fs)	WDR35	Pathogenic	criteria provided, single submitter
373022	NM_020779.4(WDR35):c.584_585del (p.Leu195fs)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3751016	NM_020779.4(WDR35):c.2713_2714del (p.Leu905fs)	WDR35	Pathogenic	criteria provided, single submitter
3759851	NM_020779.4(WDR35):c.1714C>T (p.Gln572Ter)	WDR35	Pathogenic	criteria provided, single submitter
3762513	NM_020779.4(WDR35):c.519del (p.Phe173fs)	WDR35	Pathogenic	criteria provided, single submitter
3764724	NM_020779.4(WDR35):c.1137del (p.Thr380fs)	WDR35	Pathogenic	criteria provided, single submitter
431796	NM_020779.4(WDR35):c.206G>A (p.Gly69Asp)	WDR35	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783901	NM_020779.4(WDR35):c.721_727del (p.His241fs)	WDR35	Pathogenic	criteria provided, single submitter
4785065	NM_020779.4(WDR35):c.2306G>A (p.Trp769Ter)	WDR35	Pathogenic	criteria provided, single submitter
4788990	NM_020779.4(WDR35):c.2956del (p.Ser986fs)	WDR35	Pathogenic	criteria provided, single submitter
4793548	NM_020779.4(WDR35):c.1525-2_1527dup	WDR35	Pathogenic	criteria provided, single submitter
4796627	NM_020779.4(WDR35):c.1990C>T (p.Arg664Ter)	WDR35	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
WDR35	Definitive	Autosomal recessive	cranioectodermal dysplasia 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDR35	Orphanet:1515	Cranioectodermal dysplasia
WDR35	Orphanet:498497	Short rib-polydactyly syndrome type 5
WDR35	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
SPAG17	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
SPAG17	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDR35	HGNC:29250	ENSG00000118965	Q9P2L0	WD repeat-containing protein 35	gencc,clinvar
SPAG17	HGNC:26620	ENSG00000155761	Q6Q759	Sperm-associated antigen 17	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SPAG17	Sperm-associated antigen 17	Component of the central pair apparatus of ciliary axonemes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR35	Transcription factor	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WDR35
SPAG17	Other/Unknown	no		SPAG17

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
bronchus	1
mucosa of paranasal sinus	1
right uterine tube	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR35	257	ubiquitous	marker	bronchial epithelial cell, mucosa of paranasal sinus, bronchus
SPAG17	173	broad	marker	right uterine tube, bronchial epithelial cell, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPAG17	1,801
WDR35	1,032

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR35	Q9P2L0	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPAG17	Q6Q759	64.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	1	200.3×	0.006	WDR35
Hedgehog ‘off’ state	1	178.4×	0.006	WDR35

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intramanchette transport	1	4213.0×	0.003	SPAG17
axonemal central apparatus assembly	1	1404.3×	0.004	SPAG17
manchette assembly	1	648.1×	0.005	SPAG17
intraciliary retrograde transport	1	561.7×	0.005	WDR35
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.006	SPAG17
motile cilium assembly	1	290.6×	0.006	SPAG17
intraciliary transport	1	280.9×	0.006	WDR35
protein localization to cilium	1	200.6×	0.007	WDR35
cellular response to leukemia inhibitory factor	1	79.5×	0.015	WDR35
cilium assembly	1	36.8×	0.030	WDR35
spermatogenesis	1	17.6×	0.056	SPAG17

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WDR35	0	0
SPAG17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	WDR35, SPAG17

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WDR35	0	—
SPAG17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.