Postaxial polydactyly

Summary

Postaxial polydactyly (MONDO:0020927) is a disease caused by GLI1 (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: GLI1 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	postaxial polydactyly
Mondo ID	MONDO:0020927
OMIM	174200
UMLS	C0220697
MedGen	67394
GARD	0025268
Is cancer (heuristic)	no

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › polydactyly › non-syndromic polydactyly › postaxial polydactyly

Related subtypes (9): polysyndactyly 4, synpolydactyly type 1, synpolydactyly type 2, preaxial polydactyly of fingers, postaxial polydactyly of fingers, central polydactyly of fingers, Preaxial polydactyly of toes, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, mirror-image polydactyly

Subtypes (4): postaxial polydactyly type A, postaxial polydactyly type B, polydactyly, postaxial, type A9, polydactyly, postaxial, type a10

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

10 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 3 pathogenic, 2 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
872912	NM_022893.4(BCL11A):c.148C>T (p.Gln50Ter)	BCL11A	Pathogenic	criteria provided, single submitter
691277	NM_001429.4(EP300):c.2817+186_3262-187delinsTG	EP300	Pathogenic	criteria provided, single submitter
3906258	NM_001145678.3(KIAA0825):c.2319G>A (p.Trp773Ter)	KIAA0825	Pathogenic	criteria provided, single submitter
691941	NM_014681.6(DHX34):c.466C>T (p.Gln156Ter)	DHX34	Likely pathogenic	no assertion criteria provided
3906257	NM_001145678.3(KIAA0825):c.2743_2754del (p.Gln915_Val918del)	KIAA0825	Likely pathogenic	criteria provided, single submitter
3906259	NM_001145678.3(KIAA0825):c.970G>T (p.Val324Phe)	KIAA0825	Likely pathogenic	criteria provided, single submitter
997831	NM_000264.5(PTCH1):c.2265_2268del (p.Leu756fs)	LOC100507346	Likely pathogenic	criteria provided, single submitter
2443321	NM_032437.4(EFCAB7):c.830del (p.Gly277fs)	EFCAB7	Uncertain significance	criteria provided, single submitter
2443322	NM_032437.4(EFCAB7):c.1350_1351del	EFCAB7	Uncertain significance	criteria provided, single submitter
13821	NM_000168.6(GLI3):c.2179G>A (p.Gly727Arg)	GLI3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 15 · 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
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
KIAA0825	Orphanet:93334	Postaxial polydactyly type A
EP300	Orphanet:353284	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
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

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLI1	HGNC:4317	ENSG00000111087	P08151	Zinc finger protein GLI1	gencc
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	clinvar
DHX34	HGNC:16719	ENSG00000134815	Q14147	Probable ATP-dependent RNA helicase DHX34	clinvar
KIAA0825	HGNC:28532	ENSG00000185261	Q8IV33	Uncharacterized protein KIAA0825	clinvar
EFCAB7	HGNC:29379	ENSG00000203965	A8K855	EF-hand calcium-binding domain-containing protein 7	clinvar
EP300	HGNC:3373	ENSG00000100393	Q09472	Histone acetyltransferase p300	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	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.
BCL11A	BCL11 transcription factor A	Transcription factor.
DHX34	Probable ATP-dependent RNA helicase DHX34	Probable ATP-binding RNA helicase required for nonsense-mediated decay (NMD) degradation of mRNA transcripts containing premature stop codons.
EFCAB7	EF-hand calcium-binding domain-containing protein 7	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
EP300	Histone acetyltransferase p300	Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling.
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: 5 · Unknown: 2 · 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	5	5.9×	9e-04
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
DHX34	Transcription factor	no	3.6.4.13	Helicase_C-like, Helicase-assoc_dom, DEAD/DEAH_box_helicase_dom
KIAA0825	Other/Unknown	no		DUF4495
EFCAB7	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
EP300	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory bulb	2
adrenal tissue	2
tibial nerve	1
type B pancreatic cell	1
cortical plate	1
ganglionic eminence	1
primary visual cortex	1
blood	1
left testis	1
right testis	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
bronchial epithelial cell	1
oocyte	1
secondary oocyte	1
bone marrow cell	1
colonic epithelium	1
tendon of biceps brachii	1
ventricular zone	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
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
DHX34	217	ubiquitous	marker	right testis, blood, left testis
KIAA0825	167	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, calcaneal tendon
EFCAB7	247	ubiquitous	marker	oocyte, bronchial epithelial cell, secondary oocyte
EP300	292	ubiquitous	marker	colonic epithelium, adrenal tissue, bone marrow cell
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
EP300	10,122
GLI1	4,101
GLI3	2,825
DHX34	2,501
BCL11A	2,389
EFCAB7	1,984
KIAA0825	469

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EP300	Q09472	60
BCL11A	Q9H165	17
GLI1	P08151	5
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHX34	Q14147	80.85
EFCAB7	A8K855	80.62
KIAA0825	Q8IV33	74.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 76. Enrichment computed across 7 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
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	652.6×	2e-04	GLI1, GLI3
Hedgehog ‘off’ state	2	71.4×	0.010	GLI1, GLI3
Hedgehog ‘on’ state	2	63.4×	0.010	GLI1, GLI3
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	456.8×	0.022	EP300
NFE2L2 regulating inflammation associated genes	1	456.8×	0.022	EP300
NFE2L2 regulating ER-stress associated genes	1	456.8×	0.022	EP300
NFE2L2 regulates pentose phosphate pathway genes	1	285.5×	0.022	EP300
NFE2L2 regulating MDR associated enzymes	1	285.5×	0.022	EP300
Regulation of NFE2L2 gene expression	1	285.5×	0.022	EP300
PI5P Regulates TP53 Acetylation	1	253.8×	0.022	EP300
RUNX3 regulates p14-ARF	1	228.4×	0.022	EP300
Regulation of FOXO transcriptional activity by acetylation	1	228.4×	0.022	EP300
STAT3 nuclear events downstream of ALK signaling	1	207.6×	0.022	EP300
Regulation of gene expression by Hypoxia-inducible Factor	1	190.3×	0.022	EP300
NOTCH2 intracellular domain regulates transcription	1	190.3×	0.022	EP300
Activation of the TFAP2 (AP-2) family of transcription factors	1	190.3×	0.022	EP300
ALK mutants bind TKIs	1	190.3×	0.022	BCL11A
NFE2L2 regulating tumorigenic genes	1	190.3×	0.022	EP300
RUNX3 regulates NOTCH signaling	1	163.1×	0.022	EP300
TRAF3-dependent IRF activation pathway	1	152.3×	0.022	EP300
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	142.8×	0.022	EP300
FOXO-mediated transcription of cell death genes	1	142.8×	0.022	EP300
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	134.3×	0.022	EP300
Zygotic genome activation (ZGA)	1	134.3×	0.022	EP300
Polo-like kinase mediated events	1	126.9×	0.022	EP300
Activation of SMO	1	126.9×	0.022	EFCAB7
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	1	120.2×	0.022	EP300
Formation of the embryonic stem cell BAF (esBAF) complex	1	120.2×	0.022	BCL11A
NOTCH4 Intracellular Domain Regulates Transcription	1	114.2×	0.022	EP300
Regulation of TP53 Activity through Methylation	1	108.8×	0.022	EP300

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein import into nucleus	3	210.7×	4e-05	EFCAB7, EP300, GLI3
lung development	3	99.1×	2e-04	EP300, GLI1, GLI3
positive regulation of transcription by RNA polymerase II	5	12.4×	4e-04	BCL11A, EFCAB7, EP300, GLI1, GLI3
proximal/distal pattern formation	2	216.1×	0.001	GLI1, GLI3
regulation of smoothened signaling pathway	2	208.1×	0.001	EFCAB7, GLI1
behavioral defense response	1	2808.7×	0.003	EP300
lateral ganglionic eminence cell proliferation	1	2808.7×	0.003	GLI3
negative regulation of protein oligomerization	1	2808.7×	0.003	EP300
swimming	1	2808.7×	0.003	EP300
notochord regression	1	2808.7×	0.003	GLI1
lambdoid suture morphogenesis	1	2808.7×	0.003	GLI3
sagittal suture morphogenesis	1	2808.7×	0.003	GLI3
mammary gland specification	1	2808.7×	0.003	GLI3
anterior semicircular canal development	1	2808.7×	0.003	GLI3
lateral semicircular canal development	1	2808.7×	0.003	GLI3
peptidyl-lysine propionylation	1	2808.7×	0.003	EP300
regulation of tubulin deacetylation	1	2808.7×	0.003	EP300
peptidyl-lysine crotonylation	1	2808.7×	0.003	EP300
peptidyl-lysine butyrylation	1	2808.7×	0.003	EP300
positive regulation of protein localization to ciliary membrane	1	2808.7×	0.003	EFCAB7
negative regulation of neuron remodeling	1	2808.7×	0.003	BCL11A
negative regulation of branching morphogenesis of a nerve	1	2808.7×	0.003	BCL11A
smoothened signaling pathway	2	60.4×	0.003	GLI1, GLI3
internal protein amino acid acetylation	1	1404.3×	0.004	EP300
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	1404.3×	0.004	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	1404.3×	0.004	GLI3
larynx morphogenesis	1	1404.3×	0.004	GLI3
regulation of hepatocyte proliferation	1	1404.3×	0.004	GLI1
positive regulation of neuron projection development	2	45.7×	0.005	BCL11A, EP300
ventral midline development	1	936.2×	0.005	GLI1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EP300	9	3
GLI1	1	1
BCL11A	0	0
DHX34	0	0
KIAA0825	0	0
EFCAB7	0	0
GLI3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
MOLIBRESIB	2	EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
BETULINIC ACID	1	GLI1
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300
INOBRODIB	1	EP300

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
EP300	767	Binding:763, Functional:3, ADMET:1
GLI1	44	Binding:44

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHX34	3.6.4.13	RNA helicase
EP300	2.3.1.48	histone acetyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EP300	767

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

10 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)
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
MOLIBRESIB	2	EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
BETULINIC ACID	1	GLI1
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300
INOBRODIB	1	EP300

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	2	GLI1, EP300
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	BCL11A, DHX34, KIAA0825, EFCAB7, GLI3

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)
BCL11A	0	—
DHX34	0	—
KIAA0825	0	—
EFCAB7	0	—
GLI3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.