Polydactyly of a biphalangeal thumb

Summary

Polydactyly of a biphalangeal thumb (MONDO:0008269) is a disease caused by GLI1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GLI1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polydactyly of a biphalangeal thumb
Mondo ID	MONDO:0008269
MeSH	C536332
OMIM	174400
Orphanet	93339
DOID	DOID:0060987
SNOMED CT	445216006
UMLS	C1395852
MedGen	237235
GARD	0004417
Is cancer (heuristic)	no

Also known as: polydactyly preaxial 1 · polydactyly, preaxial type 1 · PPD1 · preaxial polydactyly 1 · preaxial polydactyly type 1

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › polydactyly › non-syndromic polydactyly › preaxial polydactyly of fingers › polydactyly of a biphalangeal thumb

Related subtypes (2): polydactyly of a triphalangeal thumb, polydactyly of an index finger

Subtypes (2): polydactyly of a biphalangeal thumb, unilateral, polydactyly of a biphalangeal thumb, bilateral

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

5 retrieved; paginated sample, class counts are floors:

3 benign, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
267927	46;XY;t(4;14)(p14;q11.2)dn		Uncertain significance	criteria provided, single submitter
626906	NM_005269.3(GLI1):c.1517T>A (p.Leu506Gln)	GLI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1240928	NM_005269.3(GLI1):c.2798G>A (p.Gly933Asp)	GLI1	Benign	criteria provided, multiple submitters, no conflicts
1277191	NM_005269.3(GLI1):c.576G>A (p.Glu192=)	GLI1	Benign	criteria provided, multiple submitters, no conflicts
1285295	NM_005269.3(GLI1):c.3298G>C (p.Glu1100Gln)	GLI1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
GLI1	Strong	Autosomal dominant	postaxial polydactyly	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI1	Orphanet:289	Ellis Van Creveld syndrome
GLI1	Orphanet:93334	Postaxial polydactyly type A
GLI1	Orphanet:93335	Postaxial polydactyly type B
GLI1	Orphanet:93339	Polydactyly of a biphalangeal thumb and/or hallux

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
GLI1	HGNC:4317	ENSG00000111087	P08151	Zinc finger protein GLI1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI1	Zinc finger protein GLI1	Acts as a transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

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
olfactory bulb	1
tibial nerve	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI1	173	broad	yes	tibial nerve, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI1	4,101

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI1	P08151	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	1631.4×	0.002	GLI1
Degradation of GLI1 by the proteasome	1	223.9×	0.006	GLI1
Hedgehog ‘off’ state	1	178.4×	0.006	GLI1
Hedgehog ‘on’ state	1	158.6×	0.006	GLI1

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
notochord regression	1	16852.0×	0.002	GLI1
regulation of hepatocyte proliferation	1	8426.0×	0.002	GLI1
ventral midline development	1	5617.3×	0.002	GLI1
regulation of cerebellar granule cell precursor proliferation	1	4213.0×	0.002	GLI1
cerebellar cortex morphogenesis	1	2808.7×	0.002	GLI1
epidermal cell differentiation	1	1685.2×	0.003	GLI1
prostate gland development	1	1404.3×	0.003	GLI1
regulation of osteoblast differentiation	1	1296.3×	0.003	GLI1
positive regulation of cell cycle G1/S phase transition	1	1123.5×	0.003	GLI1
digestive tract morphogenesis	1	991.3×	0.003	GLI1
proximal/distal pattern formation	1	648.1×	0.003	GLI1
pituitary gland development	1	648.1×	0.003	GLI1
regulation of smoothened signaling pathway	1	624.1×	0.003	GLI1
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.003	GLI1
positive regulation of DNA replication	1	581.1×	0.003	GLI1
liver regeneration	1	510.7×	0.004	GLI1
dorsal/ventral pattern formation	1	421.3×	0.004	GLI1
positive regulation of smoothened signaling pathway	1	421.3×	0.004	GLI1
response to wounding	1	221.7×	0.007	GLI1
lung development	1	198.3×	0.008	GLI1
smoothened signaling pathway	1	181.2×	0.008	GLI1
spermatid development	1	145.3×	0.009	GLI1
osteoblast differentiation	1	121.2×	0.011	GLI1
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.011	GLI1
positive regulation of cell migration	1	61.7×	0.019	GLI1
positive regulation of cell population proliferation	1	33.6×	0.034	GLI1
regulation of DNA-templated transcription	1	31.6×	0.035	GLI1
positive regulation of DNA-templated transcription	1	27.9×	0.038	GLI1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	GLI1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	GLI1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLI1	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BETULINIC ACID	1	GLI1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GLI1	44	Binding:44

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

1 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)
BETULINIC ACID	1	GLI1

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	1	GLI1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.