autosomal dominant Robinow syndrome 1

Summary

autosomal dominant Robinow syndrome 1 (MONDO:0024455) is a disease caused by WNT5A (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is PCP/CE pathway (4 cohort genes).

At a glance

• Causal gene: WNT5A (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Robinow syndrome 1
Mondo ID	MONDO:0024455
OMIM	180700
DOID	DOID:0060766
UMLS	C4551475
MedGen	1641736
GARD	0002013
Is cancer (heuristic)	no

Also known as: autosomal dominant Robinow syndrome caused by mutation in WNT5A · DRS1 · dysostosis acral with facial and genital abnormalities · foetal face syndrome · Robinow syndrome, autosomal dominant 1 · WNT5A autosomal dominant Robinow syndrome

Data availability: 88 ClinVar variants · 5 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 dominant disease › autosomal dominant Robinow syndrome › autosomal dominant Robinow syndrome 1

Related subtypes (2): autosomal dominant Robinow syndrome 2, autosomal dominant Robinow syndrome 3

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

88 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 13 conflicting classifications of pathogenicity, 11 pathogenic, 7 likely benign, 7 likely pathogenic, 4 benign/likely benign, 1 benign, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208049	NM_001330311.2(DVL1):c.1637del (p.Pro546fs)	DVL1	Pathogenic	criteria provided, single submitter
219218	NM_004423.4(DVL3):c.1585del (p.Ala529fs)	DVL3	Pathogenic	criteria provided, single submitter
219219	NM_004423.4(DVL3):c.1715-2A>G	DVL3	Pathogenic	criteria provided, single submitter
219220	NM_004423.4(DVL3):c.1715-1G>A	DVL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219221	NM_004423.4(DVL3):c.1716del (p.Ser573fs)	DVL3	Pathogenic	criteria provided, single submitter
219222	NM_004423.4(DVL3):c.1749del (p.Ser583fs)	DVL3	Pathogenic	criteria provided, single submitter
694689	NM_004423.4(DVL3):c.1715-2A>C	DVL3	Pathogenic	criteria provided, single submitter
617609	NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)	FZD2	Pathogenic	criteria provided, multiple submitters, no conflicts
981470	NM_001466.4(FZD2):c.367_388dup (p.Phe130fs)	FZD2	Pathogenic	no assertion criteria provided
1065560	NM_003392.7(WNT5A):c.206G>T (p.Cys69Phe)	WNT5A	Pathogenic	criteria provided, multiple submitters, no conflicts
162612	NM_003392.7(WNT5A):c.257A>G (p.Tyr86Cys)	WNT5A	Pathogenic	criteria provided, single submitter
29820	NM_003392.7(WNT5A):c.248G>C (p.Cys83Ser)	WNT5A	Pathogenic	no assertion criteria provided
931630	NM_001330311.2(DVL1):c.1682_1683dup (p.Ser562fs)	DVL1	Likely pathogenic	criteria provided, single submitter
488061	NM_001466.4(FZD2):c.1300G>A (p.Gly434Ser)	FZD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
29819	NM_003392.7(WNT5A):c.544T>C (p.Cys182Arg)	WNT5A	Likely pathogenic	criteria provided, single submitter
3776042	NM_003392.7(WNT5A):c.247T>C (p.Cys83Arg)	WNT5A	Likely pathogenic	criteria provided, single submitter
488060	NM_003392.7(WNT5A):c.479C>G (p.Ser160Cys)	WNT5A	Likely pathogenic	criteria provided, single submitter
981471	NM_003392.7(WNT5A):c.248G>A (p.Cys83Tyr)	WNT5A	Likely pathogenic	criteria provided, single submitter
981473	NM_003392.7(WNT5A):c.247T>G (p.Cys83Gly)	WNT5A	Likely pathogenic	no assertion criteria provided
1026244	NM_001330311.2(DVL1):c.1454A>G (p.Asn485Ser)	DVL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719587	NM_001330311.2(DVL1):c.433C>T (p.Arg145Trp)	DVL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1487547	NM_003392.7(WNT5A):c.937G>A (p.Glu313Lys)	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1563096	NM_003392.7(WNT5A):c.20T>C (p.Ile7Thr)	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160310	NM_003392.7(WNT5A):c.140+14A>G	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160311	NM_003392.7(WNT5A):c.141-8C>G	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160312	NM_003392.7(WNT5A):c.141-9C>G	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160313	NM_003392.7(WNT5A):c.141-9C>T	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160314	NM_003392.7(WNT5A):c.391+11A>G	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160316	NM_003392.7(WNT5A):c.487G>C (p.Gly163Arg)	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691703	NM_003392.7(WNT5A):c.41del (p.Leu14fs)	WNT5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
WNT5A	Definitive	Autosomal dominant	autosomal dominant Robinow syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT5A	Orphanet:3107	Autosomal dominant Robinow syndrome
ROR2	Orphanet:1507	Autosomal recessive Robinow syndrome
ROR2	Orphanet:572385	Brachydactyly type B1
DVL1	Orphanet:3107	Autosomal dominant Robinow syndrome
DVL3	Orphanet:3107	Autosomal dominant Robinow syndrome
FZD2	Orphanet:3107	Autosomal dominant Robinow syndrome
FZD2	Orphanet:93328	Autosomal dominant omodysplasia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WNT5A	HGNC:12784	ENSG00000114251	P41221	Protein Wnt-5a	gencc,clinvar
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	clinvar
DVL1	HGNC:3084	ENSG00000107404	O14640	Segment polarity protein dishevelled homolog DVL-1	clinvar
DVL3	HGNC:3087	ENSG00000161202	Q92997	Segment polarity protein dishevelled homolog DVL-3	clinvar
FZD2	HGNC:4040	ENSG00000180340	Q14332	Frizzled-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT5A	Protein Wnt-5a	Ligand for members of the frizzled family of seven transmembrane receptors.
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
DVL1	Segment polarity protein dishevelled homolog DVL-1	Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors.
DVL3	Segment polarity protein dishevelled homolog DVL-3	Involved in the signal transduction pathway mediated by multiple Wnt genes.
FZD2	Frizzled-2	Receptor for Wnt proteins.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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	6.9×	0.119
Kinase	1	5.5×	0.256
GPCR	1	4.8×	0.256
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNT5A	Other/Unknown	no		Wnt, Wnt_CS, Wnt_C
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
DVL1	Scaffold/PPI	no		DEP_dom, DIX, PDZ
DVL3	Scaffold/PPI	no		DEP_dom, DIX, PDZ
FZD2	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	2
mucosa of stomach	2
decidua	1
parotid gland	1
body of uterus	1
muscle layer of sigmoid colon	1
gastrocnemius	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1
ganglionic eminence	1
dorsal root ganglion	1
embryo	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT5A	258	ubiquitous	marker	stromal cell of endometrium, parotid gland, decidua
ROR2	188	ubiquitous	marker	muscle layer of sigmoid colon, mucosa of stomach, body of uterus
DVL1	290	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, lower esophagus mucosa
DVL3	287	ubiquitous	marker	stromal cell of endometrium, ganglionic eminence, mucosa of stomach
FZD2	197	ubiquitous	marker	ventricular zone, embryo, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNT5A	3,799
DVL3	3,185
DVL1	2,949
ROR2	1,813
FZD2	1,764

Intra-cohort edges

A	B	Sources
DVL1	DVL3	intact
DVL1	FZD2	string_interaction
DVL1	ROR2	string_interaction
DVL1	WNT5A	string_interaction
DVL3	WNT5A	string_interaction
FZD2	ROR2	string_interaction
FZD2	WNT5A	string_interaction
ROR2	WNT5A	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DVL3	Q92997	9
ROR2	Q01974	6
FZD2	Q14332	5
DVL1	O14640	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WNT5A	P41221	88.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PCP/CE pathway	4	240.4×	1e-08	WNT5A, ROR2, DVL1, DVL3
WNT5:FZD7-mediated leishmania damping	3	571.0×	8e-08	WNT5A, DVL1, DVL3
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	3	527.1×	8e-08	WNT5A, ROR2, FZD2
TCF dependent signaling in response to WNT	4	94.2×	1e-07	WNT5A, DVL1, DVL3, FZD2
Disassembly of the destruction complex and recruitment of AXIN to the membrane	3	214.1×	8e-07	DVL1, DVL3, FZD2
Negative regulation of TCF-dependent signaling by DVL-interacting proteins	2	913.6×	5e-06	DVL1, DVL3
WNT mediated activation of DVL	2	571.0×	1e-05	DVL1, DVL3
Degradation of DVL	2	95.2×	4e-04	DVL1, DVL3
Asymmetric localization of PCP proteins	2	81.6×	5e-04	WNT5A, FZD2
Class B/2 (Secretin family receptors)	2	76.1×	5e-04	WNT5A, FZD2
Ca2+ pathway	2	71.4×	6e-04	WNT5A, FZD2
RHO GTPases Activate Formins	2	31.1×	0.003	DVL1, DVL3
WNT5A-dependent internalization of FZD4	1	152.3×	0.010	WNT5A
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	142.8×	0.010	WNT5A
WNT ligand biogenesis and trafficking	1	84.6×	0.016	WNT5A
Beta-catenin independent WNT signaling	1	58.6×	0.021	ROR2
Signaling by WNT	1	22.4×	0.052	ROR2
Cargo recognition for clathrin-mediated endocytosis	1	20.9×	0.052	WNT5A
Clathrin-mediated endocytosis	1	17.0×	0.060	WNT5A
Signal Transduction	1	2.0×	0.404	ROR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
non-canonical Wnt signaling pathway	4	464.9×	6e-09	WNT5A, DVL1, DVL3, FZD2
Wnt signaling pathway, planar cell polarity pathway	4	364.4×	9e-09	WNT5A, DVL1, DVL3, FZD2
positive regulation of neuron projection arborization	3	1263.9×	4e-08	WNT5A, DVL1, DVL3
canonical Wnt signaling pathway	4	122.6×	4e-07	WNT5A, DVL1, DVL3, FZD2
cochlea morphogenesis	3	348.7×	2e-06	WNT5A, DVL1, FZD2
presynapse assembly	2	481.5×	2e-04	WNT5A, DVL1
Wnt signaling pathway	3	59.8×	2e-04	WNT5A, ROR2, FZD2
regulation of postsynapse organization	2	210.7×	8e-04	WNT5A, DVL1
outflow tract morphogenesis	2	122.6×	0.002	DVL1, FZD2
heart looping	2	107.0×	0.002	WNT5A, DVL1
regulation of protein localization	2	82.2×	0.004	DVL1, DVL3
chemoattraction of serotonergic neuron axon	1	3370.4×	0.004	WNT5A
negative regulation of cell proliferation in midbrain	1	3370.4×	0.004	WNT5A
optic cup formation involved in camera-type eye development	1	1685.2×	0.004	WNT5A
chemorepulsion of dopaminergic neuron axon	1	1685.2×	0.004	WNT5A
hypophysis morphogenesis	1	1685.2×	0.004	WNT5A
positive regulation of timing of anagen	1	1685.2×	0.004	WNT5A
convergent extension involved in organogenesis	1	1685.2×	0.004	WNT5A
cervix development	1	1685.2×	0.004	WNT5A
lateral sprouting involved in mammary gland duct morphogenesis	1	1685.2×	0.004	WNT5A
postsynapse assembly	1	1685.2×	0.004	WNT5A
regulation of postsynaptic cytosolic calcium ion concentration	1	1685.2×	0.004	WNT5A
positive regulation of protein localization to presynapse	1	1685.2×	0.004	DVL1
positive regulation of JNK cascade	2	65.4×	0.004	WNT5A, DVL3
positive regulation of neuron projection development	2	54.8×	0.004	WNT5A, DVL1
positive regulation of DNA-templated transcription	3	16.8×	0.004	WNT5A, DVL3, FZD2
primary heart field specification	1	1123.5×	0.005	WNT5A
olfactory bulb interneuron development	1	1123.5×	0.005	WNT5A
convergent extension involved in neural plate elongation	1	1123.5×	0.005	DVL1
mesenchymal-epithelial cell signaling	1	1123.5×	0.005	WNT5A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WNT5A	0	0
ROR2	0	0
DVL1	0	0
DVL3	0	0
FZD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FZD2	18	Functional:18
DVL1	11	Binding:10, Functional:1
ROR2	4	Binding:4
DVL3	3	Binding:2, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROR2	2.7.10.1	receptor protein-tyrosine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	2	ROR2, FZD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	WNT5A, DVL1, DVL3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WNT5A	0	—
ROR2	4	—
DVL1	11	—
DVL3	3	—
FZD2	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.