Popliteal pterygium syndrome

Summary

Popliteal pterygium syndrome (MONDO:0017435) is a disease caused by IRF6 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: IRF6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 164

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.3	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	popliteal pterygium syndrome
Mondo ID	MONDO:0017435
MeSH	C562509
Orphanet	294963
DOID	DOID:0060055
ICD-11	543218573
NCIT	C118786
SNOMED CT	66783006
UMLS	C0265259
MedGen	78543
GARD	0021189
Is cancer (heuristic)	no

Also known as: PPS

Data availability: 164 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › congenital limb malformation › arthrogryposis syndrome › popliteal pterygium syndrome

Related subtypes (5): arthrogryposis multiplex congenita, multiple pterygium syndrome, lethal congenital contracture syndrome, distal arthrogryposis, congenital amyoplasia

Subtypes (3): autosomal dominant popliteal pterygium syndrome, Bartsocas-Papas syndrome 1, Bartsocas-Papas syndrome 2

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

164 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 48 pathogenic, 18 likely pathogenic, 16 likely benign, 10 benign, 8 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1019576	NM_006147.4(IRF6):c.1138C>T (p.Pro380Ser)	IRF6	Pathogenic	criteria provided, single submitter
1070384	NC_000001.10:g.(?209974565)(209974778_?)del	IRF6	Pathogenic	criteria provided, single submitter
1070385	NC_000001.10:g.(?209974565)(209979435_?)del	IRF6	Pathogenic	criteria provided, single submitter
1073005	NM_006147.4(IRF6):c.558C>A (p.Cys186Ter)	IRF6	Pathogenic	criteria provided, single submitter
1074446	NM_006147.4(IRF6):c.748C>T (p.Arg250Ter)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
1075467	NM_006147.4(IRF6):c.439del (p.Glu147fs)	IRF6	Pathogenic	criteria provided, single submitter
1423078	NM_006147.4(IRF6):c.1045G>T (p.Glu349Ter)	IRF6	Pathogenic	criteria provided, single submitter
1440379	NM_006147.4(IRF6):c.263A>G (p.Asn88Ser)	IRF6	Pathogenic	criteria provided, single submitter
1445221	NM_006147.4(IRF6):c.478C>T (p.Gln160Ter)	IRF6	Pathogenic	criteria provided, single submitter
1452687	NM_006147.4(IRF6):c.321_322del (p.Val108fs)	IRF6	Pathogenic	criteria provided, single submitter
1455254	NM_006147.4(IRF6):c.1052T>C (p.Phe351Ser)	IRF6	Pathogenic	criteria provided, single submitter
1456094	NM_006147.4(IRF6):c.575G>A (p.Trp192Ter)	IRF6	Pathogenic	criteria provided, single submitter
1456673	NM_006147.4(IRF6):c.647_650dup (p.Trp217fs)	IRF6	Pathogenic	criteria provided, single submitter
1459906	NM_006147.4(IRF6):c.902del (p.Gly301fs)	IRF6	Pathogenic	criteria provided, single submitter
2026633	NM_006147.4(IRF6):c.2T>A (p.Met1Lys)	IRF6	Pathogenic	criteria provided, single submitter
2050435	NM_006147.4(IRF6):c.1089del (p.Ile363fs)	IRF6	Pathogenic	criteria provided, single submitter
2104432	NM_006147.4(IRF6):c.1061-1G>T	IRF6	Pathogenic	criteria provided, single submitter
2112178	NM_006147.4(IRF6):c.56_62del (p.Asp19fs)	IRF6	Pathogenic	criteria provided, single submitter
217873	NM_006147.4(IRF6):c.1210G>A (p.Glu404Lys)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202931	NM_006147.4(IRF6):c.274G>A (p.Glu92Lys)	IRF6	Pathogenic	criteria provided, single submitter
2202932	NM_006147.4(IRF6):c.235T>C (p.Trp79Arg)	IRF6	Pathogenic	criteria provided, single submitter
2425515	NC_000001.10:g.(?209961765)(209965792_?)del	IRF6	Pathogenic	criteria provided, single submitter
254674	NM_006147.4(IRF6):c.1316T>C (p.Leu439Pro)	IRF6	Pathogenic	no assertion criteria provided
265196	NM_006147.4(IRF6):c.226C>T (p.Pro76Ser)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
2925312	NM_006147.4(IRF6):c.259C>T (p.Leu87Phe)	IRF6	Pathogenic	criteria provided, single submitter
2946861	NM_006147.4(IRF6):c.492del (p.Phe165fs)	IRF6	Pathogenic	criteria provided, single submitter
2946902	NM_006147.4(IRF6):c.430G>T (p.Glu144Ter)	IRF6	Pathogenic	criteria provided, single submitter
30652	NM_006147.4(IRF6):c.65T>C (p.Leu22Pro)	IRF6	Pathogenic	no assertion criteria provided
30653	NM_006147.4(IRF6):c.251G>T (p.Arg84Leu)	IRF6	Pathogenic	no assertion criteria provided
3411	NM_006147.4(IRF6):c.274G>T (p.Glu92Ter)	IRF6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
IRF6	Definitive	Autosomal dominant	autosomal dominant popliteal pterygium syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF6	Orphanet:1300	Autosomal dominant popliteal pterygium syndrome
IRF6	Orphanet:141291	Cleft lip and alveolus
IRF6	Orphanet:199302	Isolated cleft lip
IRF6	Orphanet:199306	Cleft lip/palate
IRF6	Orphanet:708014	Ectodermal dysplasia-natal teeth-skin abscesses-plantar hyperkeratosis-hearing impairment
IRF6	Orphanet:888	Van der Woude syndrome
IRF6	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
IRF6	HGNC:6121	ENSG00000117595	O14896	Interferon regulatory factor 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRF6	Interferon regulatory factor 6	Probable DNA-binding transcriptional activator.

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)
IRF6	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf

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
esophagus squamous epithelium	1
secondary oocyte	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRF6	228	broad	marker	secondary oocyte, upper leg skin, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRF6	1,897

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IRF6	O14896	74.19

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
Interferon alpha/beta signaling	1	152.3×	0.014	IRF6
Interferon gamma signaling	1	125.5×	0.014	IRF6
Interferon Signaling	1	120.2×	0.014	IRF6
Cytokine Signaling in Immune system	1	40.8×	0.031	IRF6
Immune System	1	13.0×	0.077	IRF6

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
mammary gland epithelial cell differentiation	1	1203.7×	0.004	IRF6
cranial skeletal system development	1	936.2×	0.004	IRF6
cell development	1	887.0×	0.004	IRF6
negative regulation of stem cell proliferation	1	842.6×	0.004	IRF6
negative regulation of keratinocyte proliferation	1	702.2×	0.004	IRF6
keratinocyte proliferation	1	581.1×	0.004	IRF6
limb development	1	411.0×	0.005	IRF6
immune system process	1	391.9×	0.005	IRF6
stem cell proliferation	1	312.1×	0.005	IRF6
keratinocyte differentiation	1	247.8×	0.006	IRF6
roof of mouth development	1	247.8×	0.006	IRF6
negative regulation of cell population proliferation	1	42.1×	0.030	IRF6
positive regulation of DNA-templated transcription	1	27.9×	0.041	IRF6
positive regulation of transcription by RNA polymerase II	1	14.9×	0.072	IRF6
regulation of transcription by RNA polymerase II	1	11.7×	0.086	IRF6

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
IRF6	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	IRF6

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)
IRF6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.