Polysyndactyly 4

Summary

Polysyndactyly 4 (MONDO:0008272) is a disease caused by GLI3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GLI3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 262

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polysyndactyly 4
Mondo ID	MONDO:0008272
OMIM	174700
Orphanet	93338
DOID	DOID:0060985
ICD-11	973656080
UMLS	C1868111
MedGen	357420
GARD	0009903
MedDRA	10063143
Is cancer (heuristic)	no

Also known as: crossed polydactyly type 1 · polydactyly preaxial 4 · polydactyly, preaxial type 4 · polydactyly, preaxial, type IV · polysyndactyly uncomplicated · PPD4 · preaxial polydactyly 4 · preaxial polydactyly type 4

Data availability: 262 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 › syndactyly › non-syndromic syndactyly › non-syndromic synpolydactyly › polysyndactyly 4

Related subtypes (3): synpolydactyly type 1, synpolydactyly type 2, synpolydactyly type 3

Subtypes (2): polysyndactyly, unilateral, polysyndactyly, 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

262 retrieved; paginated sample, class counts are floors:

140 uncertain significance, 57 conflicting classifications of pathogenicity, 27 benign/likely benign, 21 likely benign, 9 pathogenic, 5 benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120234	NM_000168.6(GLI3):c.1880_1881del (p.His627fs)	GLI3	Pathogenic	criteria provided, multiple submitters, no conflicts
13817	NM_000168.6(GLI3):c.3646dup (p.Leu1216fs)	GLI3	Pathogenic	no assertion criteria provided
13826	NM_000168.6(GLI3):c.868C>T (p.Arg290Ter)	GLI3	Pathogenic	criteria provided, multiple submitters, no conflicts
13828	NM_000168.6(GLI3):c.2374C>T (p.Arg792Ter)	GLI3	Pathogenic	criteria provided, multiple submitters, no conflicts
1695390	NM_000168.6(GLI3):c.1673C>A (p.Ser558Ter)	GLI3	Pathogenic	criteria provided, single submitter
1699074	NM_000168.6(GLI3):c.438C>G (p.Tyr146Ter)	GLI3	Pathogenic	criteria provided, single submitter
3382660	NM_000168.6(GLI3):c.2128C>T (p.Gln710Ter)	GLI3	Pathogenic	criteria provided, single submitter
3392509	NM_000168.6(GLI3):c.999_1002dup (p.Gly335fs)	GLI3	Pathogenic	criteria provided, single submitter
4531290	NM_000168.6(GLI3):c.1681G>T (p.Glu561Ter)	GLI3	Pathogenic	criteria provided, single submitter
3062247	NM_000168.6(GLI3):c.1325_1328dup (p.Ser445fs)	GLI3	Likely pathogenic	criteria provided, single submitter
3062311	NM_000168.6(GLI3):c.2876_2880dup (p.Gly961fs)	GLI3	Likely pathogenic	criteria provided, single submitter
3067137	NM_000168.6(GLI3):c.2151del (p.Gln717fs)	GLI3	Likely pathogenic	criteria provided, single submitter
1040568	NM_000168.6(GLI3):c.3611C>G (p.Pro1204Arg)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343294	NM_000168.6(GLI3):c.233C>T (p.Ser78Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343295	NM_000168.6(GLI3):c.245G>A (p.Arg82Lys)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395467	NM_000168.6(GLI3):c.1159T>C (p.Phe387Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1405645	NM_000168.6(GLI3):c.4292C>T (p.Pro1431Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1447837	NM_000168.6(GLI3):c.4427A>T (p.Asn1476Ile)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448811	NM_000168.6(GLI3):c.3557C>T (p.Pro1186Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1564240	NM_000168.6(GLI3):c.1325A>G (p.Asp442Gly)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1611841	NM_000168.6(GLI3):c.2308G>T (p.Ala770Ser)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1919661	NM_000168.6(GLI3):c.1954C>A (p.Pro652Thr)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2039161	NM_000168.6(GLI3):c.474-3C>T	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2048457	NM_000168.6(GLI3):c.3569C>T (p.Ala1190Val)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2075378	NM_000168.6(GLI3):c.3286G>A (p.Val1096Met)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2082732	NM_000168.6(GLI3):c.1471T>C (p.Phe491Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2084549	NM_000168.6(GLI3):c.2408C>T (p.Ala803Val)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211083	NM_000168.6(GLI3):c.3695A>C (p.His1232Pro)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2149763	NM_000168.6(GLI3):c.2000G>A (p.Arg667Gln)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2196176	NM_000168.6(GLI3):c.2083G>T (p.Val695Phe)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
GLI3	Strong	Autosomal dominant	polysyndactyly 4	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

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
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

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)
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
olfactory bulb	1
tendon of biceps brachii	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI3	2,825

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI3	P10071	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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×	0.003	GLI3
RUNX2 regulates osteoblast differentiation	1	456.8×	0.005	GLI3
GLI3 is processed to GLI3R by the proteasome	1	223.9×	0.006	GLI3
Hedgehog ‘off’ state	1	178.4×	0.006	GLI3
Hedgehog ‘on’ state	1	158.6×	0.006	GLI3

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
lateral ganglionic eminence cell proliferation	1	16852.0×	7e-04	GLI3
lambdoid suture morphogenesis	1	16852.0×	7e-04	GLI3
sagittal suture morphogenesis	1	16852.0×	7e-04	GLI3
mammary gland specification	1	16852.0×	7e-04	GLI3
anterior semicircular canal development	1	16852.0×	7e-04	GLI3
lateral semicircular canal development	1	16852.0×	7e-04	GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	8426.0×	9e-04	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	8426.0×	9e-04	GLI3
larynx morphogenesis	1	8426.0×	9e-04	GLI3
nose morphogenesis	1	5617.3×	1e-03	GLI3
negative regulation of alpha-beta T cell differentiation	1	5617.3×	1e-03	GLI3
frontal suture morphogenesis	1	5617.3×	1e-03	GLI3
cell differentiation involved in kidney development	1	5617.3×	1e-03	GLI3
hindgut morphogenesis	1	4213.0×	0.001	GLI3
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	4213.0×	0.001	GLI3
optic nerve morphogenesis	1	3370.4×	0.001	GLI3
regulation of bone development	1	3370.4×	0.001	GLI3
forebrain radial glial cell differentiation	1	2808.7×	0.001	GLI3
forebrain dorsal/ventral pattern formation	1	2106.5×	0.002	GLI3
tongue development	1	2106.5×	0.002	GLI3
alpha-beta T cell differentiation	1	1872.4×	0.002	GLI3
embryonic neurocranium morphogenesis	1	1872.4×	0.002	GLI3
positive regulation of alpha-beta T cell differentiation	1	1685.2×	0.002	GLI3
negative thymic T cell selection	1	1404.3×	0.002	GLI3
artery development	1	1404.3×	0.002	GLI3
thymocyte apoptotic process	1	1404.3×	0.002	GLI3
layer formation in cerebral cortex	1	1123.5×	0.002	GLI3
limb morphogenesis	1	1053.2×	0.002	GLI3
embryonic digestive tract development	1	991.3×	0.002	GLI3
embryonic digestive tract morphogenesis	1	936.2×	0.003	GLI3

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
GLI3	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	GLI3

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)
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.