Split hand-foot malformation 6

Summary

Split hand-foot malformation 6 (MONDO:0009157) is a disease caused by WNT10B (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: WNT10B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	split hand-foot malformation 6
Mondo ID	MONDO:0009157
MeSH	C567616
OMIM	225300
DOID	DOID:0090026
UMLS	C2749665
MedGen	440845
GARD	0015166
Is cancer (heuristic)	no

Also known as: SHFM6 · split hand-foot malformation caused by mutation in WNT10B · split hand-foot malformation type 6 · split-hand/foot malformation 6 · split-hand/foot malformation type 6 · WNT10B split hand-foot malformation

Data availability: 25 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › split hand-foot malformation › split hand-foot malformation 6

Related subtypes (5): split hand-foot malformation 1, split hand-foot malformation 3, split hand-foot malformation 2, split hand-foot malformation 4, split hand-foot malformation 5

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

25 retrieved; paginated sample, class counts are floors:

9 likely pathogenic, 8 pathogenic, 5 uncertain significance, 1 benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333232	NM_003394.4(WNT10B):c.117_136del (p.Glu39fs)	WNT10B	Pathogenic	criteria provided, single submitter
1695395	NM_003394.4(WNT10B):c.741del (p.Lys246_Cys247insTer)	WNT10B	Pathogenic	criteria provided, multiple submitters, no conflicts
1698374	NM_003394.4(WNT10B):c.499_500del (p.Leu167fs)	WNT10B	Pathogenic	criteria provided, single submitter
30237	NM_003394.4(WNT10B):c.458_461dup (p.Asp155fs)	WNT10B	Pathogenic	no assertion criteria provided
3376605	NM_003394.4(WNT10B):c.343C>T (p.Arg115Ter)	WNT10B	Pathogenic	criteria provided, single submitter
522440	NM_003394.4(WNT10B):c.676C>T (p.Arg226Ter)	WNT10B	Pathogenic	criteria provided, single submitter
545118	NM_003394.4(WNT10B):c.338-1G>C	WNT10B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634645	NM_003394.4(WNT10B):c.817del (p.Ala273fs)	WNT10B	Pathogenic	no assertion criteria provided
7630	NM_003394.4(WNT10B):c.994C>T (p.Arg332Trp)	WNT10B	Pathogenic	criteria provided, single submitter
2502298	NM_003394.4(WNT10B):c.53T>A (p.Leu18Gln)	WNT10B	Likely pathogenic	criteria provided, single submitter
2664721	NM_003394.4(WNT10B):c.115G>T (p.Glu39Ter)	WNT10B	Likely pathogenic	criteria provided, single submitter
3391173	NM_003394.4(WNT10B):c.638T>G (p.Phe213Cys)	WNT10B	Likely pathogenic	criteria provided, single submitter
4291871	NM_003394.4(WNT10B):c.148dup (p.Thr50fs)	WNT10B	Likely pathogenic	criteria provided, single submitter
4845799	NM_003394.4(WNT10B):c.337_337+1delinsTGTGAGGA	WNT10B	Likely pathogenic	criteria provided, single submitter
599263	NM_003394.4(WNT10B):c.689ACA[2] (p.Asn232del)	WNT10B	Likely pathogenic	criteria provided, single submitter
634646	NM_003394.4(WNT10B):c.746G>T (p.Cys249Phe)	WNT10B	Likely pathogenic	no assertion criteria provided
634648	NM_003394.4(WNT10B):c.949T>A (p.Phe317Ile)	WNT10B	Likely pathogenic	no assertion criteria provided
638164	NM_003394.4(WNT10B):c.257A>C (p.Gln86Pro)	WNT10B	Likely pathogenic	no assertion criteria provided
3382089	NM_003394.4(WNT10B):c.523del (p.His175fs)	WNT10B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1895401	NM_003394.4(WNT10B):c.337G>C (p.Gly113Arg)	WNT10B	Uncertain significance	criteria provided, single submitter
4293161	NM_003394.4(WNT10B):c.746G>A (p.Cys249Tyr)	WNT10B	Uncertain significance	criteria provided, single submitter
493116	NM_003394.4(WNT10B):c.995G>A (p.Arg332Gln)	WNT10B	Uncertain significance	criteria provided, multiple submitters, no conflicts
623323	NM_003394.4(WNT10B):c.290T>C (p.Leu97Pro)	WNT10B	Uncertain significance	criteria provided, single submitter
634647	NM_003394.4(WNT10B):c.817dup (p.Ala273fs)	WNT10B	Uncertain significance	criteria provided, single submitter
1175136	NM_003394.4(WNT10B):c.1059C>T (p.His353=)	WNT10B	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
WNT10B	Definitive	Autosomal recessive	split hand-foot malformation 6	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT10B	Orphanet:2440	Isolated split hand-split foot malformation
WNT10B	Orphanet:99798	Oligodontia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WNT10B	HGNC:12775	ENSG00000169884	O00744	Protein Wnt-10b	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT10B	Protein Wnt-10b	Member of the Wnt ligand gene family that encodes for secreted proteins, which activate the Wnt signaling cascade.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNT10B	Other/Unknown	no		Wnt, Wnt10, Wnt_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT10B	197	broad	marker	type B pancreatic cell, olfactory bulb, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNT10B	1,267

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WNT10B	O00744	80.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
WNT ligand biogenesis and trafficking	1	423.0×	0.007	WNT10B
Class B/2 (Secretin family receptors)	1	190.3×	0.008	WNT10B
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.008	WNT10B

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fungiform papilla development	1	16852.0×	0.001	WNT10B
myoblast differentiation involved in skeletal muscle regeneration	1	8426.0×	0.001	WNT10B
regulation of skeletal muscle tissue development	1	8426.0×	0.001	WNT10B
positive regulation of timing of anagen	1	8426.0×	0.001	WNT10B
myoblast development	1	4213.0×	0.002	WNT10B
positive regulation of RNA polymerase II transcription preinitiation complex assembly	1	3370.4×	0.002	WNT10B
bone trabecula formation	1	2106.5×	0.002	WNT10B
positive regulation of epithelial cell differentiation	1	1872.4×	0.002	WNT10B
positive regulation of hematopoietic stem cell proliferation	1	1872.4×	0.002	WNT10B
cellular response to parathyroid hormone stimulus	1	1404.3×	0.003	WNT10B
regulation of proteasomal ubiquitin-dependent protein catabolic process	1	1123.5×	0.003	WNT10B
sensory perception of taste	1	1123.5×	0.003	WNT10B
hematopoietic stem cell proliferation	1	648.1×	0.005	WNT10B
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.005	WNT10B
skeletal muscle fiber development	1	543.6×	0.005	WNT10B
positive regulation of T cell differentiation	1	455.5×	0.005	WNT10B
positive regulation of bone mineralization	1	391.9×	0.005	WNT10B
T cell differentiation	1	383.0×	0.005	WNT10B
negative regulation of cold-induced thermogenesis	1	343.9×	0.005	WNT10B
G2/M transition of mitotic cell cycle	1	312.1×	0.005	WNT10B
negative regulation of fat cell differentiation	1	312.1×	0.005	WNT10B
chondrocyte differentiation	1	300.9×	0.005	WNT10B
cell fate commitment	1	295.6×	0.005	WNT10B
negative regulation of epithelial cell proliferation	1	290.6×	0.005	WNT10B
cellular response to cAMP	1	290.6×	0.005	WNT10B
cellular response to retinoic acid	1	234.1×	0.006	WNT10B
positive regulation of osteoblast differentiation	1	224.7×	0.006	WNT10B
smoothened signaling pathway	1	181.2×	0.007	WNT10B
fat cell differentiation	1	181.2×	0.007	WNT10B
epithelial cell differentiation	1	175.5×	0.007	WNT10B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
WNT10B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	WNT10B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WNT10B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.