autosomal dominant Robinow syndrome 2

Summary

autosomal dominant Robinow syndrome 2 (MONDO:0014591) is a disease caused by DVL1 (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is Disassembly of the destruction complex and recruitment of AXIN to the membrane (3 cohort genes).

At a glance

• Causal gene: DVL1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Robinow syndrome 2
Mondo ID	MONDO:0014591
OMIM	616331
DOID	DOID:0060765
UMLS	C4225363
MedGen	897039
GARD	0018548
Is cancer (heuristic)	no

Also known as: autosomal dominant Robinow syndrome caused by mutation in DVL1 · autosomal dominant Robinow syndrome type 2 · DRS2 · DVL1 autosomal dominant Robinow syndrome · Robinow syndrome, autosomal dominant 2 · Robinow syndrome, autosomal dominant type 2

Data availability: 63 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 dominant disease › autosomal dominant Robinow syndrome › autosomal dominant Robinow syndrome 2

Related subtypes (2): autosomal dominant Robinow syndrome 3, autosomal dominant Robinow syndrome 1

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

63 retrieved; paginated sample, class counts are floors:

19 pathogenic, 13 uncertain significance, 9 conflicting classifications of pathogenicity, 8 likely pathogenic, 6 benign, 4 likely benign, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
974781	NM_001822.7(CHN1):c.1106T>G (p.Ile369Ser)	CHN1	Pathogenic	no assertion criteria provided
208043	NM_001330311.2(DVL1):c.1645_1646delinsC (p.Phe549fs)	DVL1	Pathogenic	criteria provided, single submitter
208044	NM_001330311.2(DVL1):c.1580_1592del (p.His527fs)	DVL1	Pathogenic	criteria provided, single submitter
208045	NM_001330311.2(DVL1):c.1594del (p.Trp532fs)	DVL1	Pathogenic	criteria provided, multiple submitters, no conflicts
208046	NM_001330311.2(DVL1):c.1583del (p.Pro528fs)	DVL1	Pathogenic	criteria provided, single submitter
208047	NM_001330311.2(DVL1):c.1690del (p.Ser564fs)	DVL1	Pathogenic	criteria provided, single submitter
208048	NM_001330311.2(DVL1):c.1604del (p.Gly535fs)	DVL1	Pathogenic	criteria provided, single submitter
208049	NM_001330311.2(DVL1):c.1637del (p.Pro546fs)	DVL1	Pathogenic	criteria provided, single submitter
208050	NM_001330311.2(DVL1):c.1651_1658delinsG (p.Pro551fs)	DVL1	Pathogenic	no assertion criteria provided
219223	NM_001330311.2(DVL1):c.1598del (p.Pro533fs)	DVL1	Pathogenic	criteria provided, single submitter
3764194	NM_001330311.2(DVL1):c.1695del (p.Ser567fs)	DVL1	Pathogenic	criteria provided, multiple submitters, no conflicts
488047	NM_001330311.2(DVL1):c.1571_1583del (p.Pro524fs)	DVL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807594	NM_001330311.2(DVL1):c.1547del (p.Thr516fs)	DVL1	Pathogenic	criteria provided, single submitter
981467	NM_001330311.2(DVL1):c.1667del (p.Pro556fs)	DVL1	Pathogenic	no assertion criteria provided
984981	NM_001330311.2(DVL1):c.1631del (p.Gly544fs)	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
419236	NM_001377.3(DYNC2H1):c.5983G>A (p.Ala1995Thr)	DYNC2H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617609	NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)	FZD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1709442	NM_001330311.2(DVL1):c.363-1G>C	DVL1	Likely pathogenic	criteria provided, single submitter
488045	NM_001330311.2(DVL1):c.1687_1691dup (p.Ser564fs)	DVL1	Likely pathogenic	criteria provided, single submitter
488046	NM_001330311.2(DVL1):c.1698del (p.Ser567fs)	DVL1	Likely pathogenic	criteria provided, single submitter
981468	NM_001330311.2(DVL1):c.1715-1G>A	DVL1	Likely pathogenic	no assertion criteria provided
488049	NM_004423.4(DVL3):c.1617del (p.Gln539fs)	DVL3	Likely pathogenic	criteria provided, single submitter
488052	NM_001466.4(FZD2):c.1301_1302delinsTT (p.Gly434Val)	FZD2	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
488048	NM_001330311.2(DVL1):c.1683_1698del (p.Ser562fs)	LOC129929114	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 9 · 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
DVL1	Definitive	Autosomal dominant	autosomal dominant Robinow syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DVL1	Orphanet:3107	Autosomal dominant Robinow syndrome
CHN1	Orphanet:233	Duane retraction syndrome
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
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
DVL1	HGNC:3084	ENSG00000107404	O14640	Segment polarity protein dishevelled homolog DVL-1	gencc,clinvar
CHN1	HGNC:1943	ENSG00000128656	P15882	N-chimaerin	clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 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)
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.
CHN1	N-chimaerin	GTPase-activating protein for p21-rac and a phorbol ester receptor.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
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: 1 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.2

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	3	10.4×	0.005
GPCR	1	4.8×	0.288
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DVL1	Scaffold/PPI	no		DEP_dom, DIX, PDZ
CHN1	Scaffold/PPI	no		RhoGAP_dom, SH2, PKC_DAG/PE
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
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
gastrocnemius	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
bronchial epithelial cell	1
right uterine tube	1
secondary oocyte	1
ganglionic eminence	1
mucosa of stomach	1
stromal cell of endometrium	1
dorsal root ganglion	1
embryo	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DVL1	290	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, lower esophagus mucosa
CHN1	279	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
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: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DVL3	3,185
DVL1	2,949
DYNC2H1	1,885
FZD2	1,764
CHN1	1,091

Intra-cohort edges

A	B	Sources
DVL1	DVL3	intact
DVL1	FZD2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DVL3	Q92997	9
FZD2	Q14332	5
DYNC2H1	Q8NCM8	4
DVL1	O14640	3
CHN1	P15882	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Disassembly of the destruction complex and recruitment of AXIN to the membrane	3	214.1×	3e-06	DVL1, DVL3, FZD2
Negative regulation of TCF-dependent signaling by DVL-interacting proteins	2	913.6×	1e-05	DVL1, DVL3
WNT mediated activation of DVL	2	571.0×	2e-05	DVL1, DVL3
TCF dependent signaling in response to WNT	3	70.6×	2e-05	DVL1, DVL3, FZD2
WNT5:FZD7-mediated leishmania damping	2	380.7×	3e-05	DVL1, DVL3
PCP/CE pathway	2	120.2×	3e-04	DVL1, DVL3
Degradation of DVL	2	95.2×	4e-04	DVL1, DVL3
RHO GTPases Activate Formins	2	31.1×	0.003	DVL1, DVL3
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	175.7×	0.010	FZD2
Asymmetric localization of PCP proteins	1	40.8×	0.032	FZD2
Intraflagellar transport	1	40.1×	0.032	DYNC2H1
Class B/2 (Secretin family receptors)	1	38.1×	0.032	FZD2
Ca2+ pathway	1	35.7×	0.032	FZD2
Hedgehog ‘off’ state	1	35.7×	0.032	DYNC2H1
CDC42 GTPase cycle	1	14.5×	0.072	CHN1
RAC1 GTPase cycle	1	12.2×	0.079	CHN1

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	3	348.7×	3e-06	DVL1, DVL3, FZD2
Wnt signaling pathway, planar cell polarity pathway	3	273.3×	3e-06	DVL1, DVL3, FZD2
positive regulation of neuron projection arborization	2	842.6×	5e-05	DVL1, DVL3
canonical Wnt signaling pathway	3	91.9×	5e-05	DVL1, DVL3, FZD2
cochlea morphogenesis	2	232.4×	4e-04	DVL1, FZD2
outflow tract morphogenesis	2	122.6×	0.001	DVL1, FZD2
regulation of protein localization	2	82.2×	0.002	DVL1, DVL3
positive regulation of protein localization to presynapse	1	1685.2×	0.005	DVL1
convergent extension involved in neural plate elongation	1	1123.5×	0.007	DVL1
muscular septum morphogenesis	1	674.1×	0.010	FZD2
inner ear receptor cell development	1	481.5×	0.013	FZD2
protein stabilization	2	26.8×	0.013	DVL1, DVL3
skeletal muscle acetylcholine-gated channel clustering	1	374.5×	0.014	DVL1
membranous septum morphogenesis	1	337.0×	0.014	FZD2
hard palate development	1	337.0×	0.014	FZD2
protein localization to microtubule	1	259.3×	0.015	DVL1
collateral sprouting	1	240.7×	0.015	DVL1
presynapse assembly	1	240.7×	0.015	DVL1
intraciliary retrograde transport	1	224.7×	0.015	DYNC2H1
endothelial cell differentiation	1	224.7×	0.015	FZD2
prepulse inhibition	1	224.7×	0.015	DVL1
spinal cord motor neuron differentiation	1	187.2×	0.016	DYNC2H1
regulation of axonogenesis	1	177.4×	0.016	CHN1
dendritic spine morphogenesis	1	177.4×	0.016	DVL1
synaptic vesicle exocytosis	1	153.2×	0.018	DVL1
neurotransmitter secretion	1	140.4×	0.018	DVL1
motor neuron axon guidance	1	140.4×	0.018	CHN1
cilium movement involved in cell motility	1	134.8×	0.018	DYNC2H1
receptor clustering	1	124.8×	0.019	DVL1
coronary vasculature development	1	124.8×	0.019	DYNC2H1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DVL1	0	0
CHN1	0	0
DYNC2H1	0	0
DVL3	0	0
FZD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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

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	1	FZD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	DVL1, CHN1, DYNC2H1, 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)
DVL1	11	—
CHN1	0	—
DYNC2H1	0	—
DVL3	3	—
FZD2	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.