postaxial polydactyly type A

Summary

postaxial polydactyly type A (MONDO:0019673) is a disease (an umbrella term covering 10 Mondo subtypes) with 6 cohort genes. The dominant Reactome pathway is Hedgehog ‘on’ state (3 cohort genes).

At a glance

• Prevalence: 1-5 / 10 000 (Mexico) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	15.7	Mexico	Validated
Prevalence at birth	1-5 / 10 000	15.7	Mexico	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	postaxial polydactyly type A
Mondo ID	MONDO:0019673
Orphanet	93334
ICD-11	476330894
SNOMED CT	715704001
UMLS	C3887487
MedGen	854350
GARD	0016817
Is cancer (heuristic)	no

Also known as: PAPA · postaxial polydactyly type A · postaxial polydactyly type A (disease)

Data availability: 2 ClinVar variants · 6 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 10 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 › postaxial polydactyly type A

Related subtypes (3): postaxial polydactyly type B, polydactyly, postaxial, type A9, polydactyly, postaxial, type a10

Subtypes (10): polydactyly, postaxial, type A1, polydactyly, postaxial, type A5, polydactyly, postaxial, type A2, polydactyly, postaxial, type A3, polydactyly, postaxial, type A4, polydactyly, postaxial, type A6, postaxial polydactyly type A, unilateral, postaxial polydactyly type A, bilateral, polydactyly, postaxial, type A8, polydactyly, postaxial, type a7

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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
592165	NM_145269.5(CIBAR1):c.478C>T (p.Arg160Ter)	CIBAR1	Pathogenic	criteria provided, multiple submitters, no conflicts
2502320	NM_000168.6(GLI3):c.4332T>A (p.Tyr1444Ter)	GLI3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · 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
GLI3	Strong	Autosomal dominant	polydactyly, postaxial, type A1	21
IQCE	Strong	Autosomal recessive	polydactyly, postaxial, type a7	4
KIAA0825	Strong	Autosomal recessive	polydactyly, postaxial, type a10	4
CIBAR1	Moderate	Autosomal recessive	polydactyly, postaxial, type A9	3
ZNF141	Supportive	Autosomal recessive	postaxial polydactyly type A	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CIBAR1	Orphanet:93334	Postaxial polydactyly type A
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
ZNF141	Orphanet:93334	Postaxial polydactyly type A
KIAA0825	Orphanet:93334	Postaxial polydactyly type A
IQCE	Orphanet:93334	Postaxial polydactyly type A
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

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CIBAR1	HGNC:30452	ENSG00000188343	A1XBS5	CBY1-interacting BAR domain-containing protein 1	gencc,clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	gencc,clinvar
ZNF141	HGNC:12926	ENSG00000131127	Q15928	Zinc finger protein 141	gencc
KIAA0825	HGNC:28532	ENSG00000185261	Q8IV33	Uncharacterized protein KIAA0825	gencc
IQCE	HGNC:29171	ENSG00000106012	Q6IPM2	IQ domain-containing protein E	gencc
GLI1	HGNC:4317	ENSG00000111087	P08151	Zinc finger protein GLI1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIBAR1	CBY1-interacting BAR domain-containing protein 1	Plays a critical role in regulating mitochondrial ultrastructure and function by maintaining the integrity of mitochondrial morphology, particularly the organization of cristae.
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.
ZNF141	Zinc finger protein 141	May be involved in transcriptional regulation as a repressor.
IQCE	IQ domain-containing protein E	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
GLI1	Zinc finger protein GLI1	Acts as a transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 4 · 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	3	4.1×	0.080
Scaffold/PPI	1	2.9×	0.451
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIBAR1	Scaffold/PPI	no		CBAR/FAM92, AH/BAR_dom_sf, BAR_CBAR1/2
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
ZNF141	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
KIAA0825	Other/Unknown	no		DUF4495
IQCE	Other/Unknown	no		IQ_motif_EF-hand-BS, CellDiv_DevSignal_Domain
GLI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
right testis	2
olfactory bulb	2
adrenal tissue	2
calcaneal tendon	2
testis	1
tendon of biceps brachii	1
ventricular zone	1
tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1
tibial nerve	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIBAR1	229	ubiquitous	marker	left testis, right testis, testis
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii
ZNF141	209	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
KIAA0825	167	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, calcaneal tendon
IQCE	231	ubiquitous	marker	left testis, right testis, sural nerve
GLI1	173	broad	yes	tibial nerve, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI1	4,101
GLI3	2,825
IQCE	1,124
CIBAR1	744
KIAA0825	469
ZNF141	419

Intra-cohort edges

A	B	Sources
CIBAR1	IQCE	string_interaction
CIBAR1	KIAA0825	string_interaction
CIBAR1	ZNF141	string_interaction
GLI1	IQCE	string_interaction
IQCE	KIAA0825	string_interaction
IQCE	ZNF141	string_interaction
KIAA0825	ZNF141	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLI1	P08151	5
CIBAR1	A1XBS5	1
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIAA0825	Q8IV33	74.33
ZNF141	Q15928	70.46
IQCE	Q6IPM2	69.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hedgehog ‘on’ state	3	119.0×	1e-05	GLI3, IQCE, GLI1
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	815.7×	1e-05	GLI3, GLI1
Hedgehog ‘off’ state	2	89.2×	7e-04	GLI3, GLI1
Activation of SMO	1	158.6×	0.017	IQCE
RUNX2 regulates osteoblast differentiation	1	114.2×	0.019	GLI3
Degradation of GLI1 by the proteasome	1	56.0×	0.028	GLI1
GLI3 is processed to GLI3R by the proteasome	1	56.0×	0.028	GLI3
Signaling by Hedgehog	1	46.0×	0.030	IQCE
Regulation of endogenous retroelements by KRAB-ZFP proteins	1	26.7×	0.045	ZNF141
Generic Transcription Pathway	1	3.8×	0.264	ZNF141
Signal Transduction	1	2.5×	0.339	IQCE

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
limb morphogenesis	4	842.6×	3e-10	CIBAR1, GLI3, ZNF141, IQCE
proximal/distal pattern formation	2	259.3×	0.001	GLI3, GLI1
positive regulation of smoothened signaling pathway	2	168.5×	0.002	CIBAR1, GLI1
lateral ganglionic eminence cell proliferation	1	3370.4×	0.002	GLI3
notochord regression	1	3370.4×	0.002	GLI1
lambdoid suture morphogenesis	1	3370.4×	0.002	GLI3
sagittal suture morphogenesis	1	3370.4×	0.002	GLI3
mammary gland specification	1	3370.4×	0.002	GLI3
anterior semicircular canal development	1	3370.4×	0.002	GLI3
lateral semicircular canal development	1	3370.4×	0.002	GLI3
lung development	2	79.3×	0.002	GLI3, GLI1
smoothened signaling pathway	2	72.5×	0.002	GLI3, GLI1
regulation of DNA-templated transcription	3	18.9×	0.002	GLI3, ZNF141, GLI1
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	1685.2×	0.003	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	1685.2×	0.003	GLI3
larynx morphogenesis	1	1685.2×	0.003	GLI3
regulation of hepatocyte proliferation	1	1685.2×	0.003	GLI1
ventral midline development	1	1123.5×	0.004	GLI1
nose morphogenesis	1	1123.5×	0.004	GLI3
negative regulation of alpha-beta T cell differentiation	1	1123.5×	0.004	GLI3
frontal suture morphogenesis	1	1123.5×	0.004	GLI3
cell differentiation involved in kidney development	1	1123.5×	0.004	GLI3
membrane tubulation	1	1123.5×	0.004	CIBAR1
osteoblast differentiation	2	48.5×	0.004	GLI3, GLI1
negative regulation of canonical Wnt signaling pathway	2	47.1×	0.004	GLI3, GLI1
hindgut morphogenesis	1	842.6×	0.004	GLI3
regulation of cerebellar granule cell precursor proliferation	1	842.6×	0.004	GLI1
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	842.6×	0.004	GLI3
optic nerve morphogenesis	1	674.1×	0.005	GLI3
regulation of bone development	1	674.1×	0.005	GLI3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 6 evidence-associated genes (17%) 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
CIBAR1	0	0
GLI3	0	0
ZNF141	0	0
KIAA0825	0	0
IQCE	0	0

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: 6; 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	5	CIBAR1, GLI3, ZNF141, KIAA0825, IQCE

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)
CIBAR1	0	—
GLI3	0	—
ZNF141	0	—
KIAA0825	0	—
IQCE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.