Autosomal dominant popliteal pterygium syndrome

Summary

Autosomal dominant popliteal pterygium syndrome (MONDO:0007334) is a disease caused by IRF6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IRF6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 14
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.3	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0002230	Generalized hirsutism	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000046	Small scrotum	Frequent (30-79%)
HP:0000048	Bifid scrotum	Frequent (30-79%)
HP:0000059	Hypoplastic labia majora	Frequent (30-79%)
HP:0000772	Abnormal rib morphology	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0006101	Finger syndactyly	Frequent (30-79%)
HP:0008288	Nonketotic hyperglycinemia	Frequent (30-79%)
HP:0009754	Fibrous syngnathia	Frequent (30-79%)
HP:0009755	Ankyloblepharon	Frequent (30-79%)
HP:0009756	Popliteal pterygium	Frequent (30-79%)
HP:0100267	Lip pit	Frequent (30-79%)
HP:0100335	Non-midline cleft of the upper lip	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0000453	Choanal atresia	Occasional (5-29%)
HP:0001171	Split hand	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant popliteal pterygium syndrome
Mondo ID	MONDO:0007334
OMIM	119500
Orphanet	1300
ICD-11	2069589860
SNOMED CT	718222000
UMLS	C5848052
MedGen	1844082
GARD	0003242
Is cancer (heuristic)	no

Also known as: cleft lip/palate paramedian mucous cysts of the lower lip popliteal pterygium digital and genital anomalies · facio-genito-popliteal syndrome · popliteal pterygium syndrome · popliteal pterygium syndrome 1 · popliteal pterygium syndrome, autosomal dominant · popliteal web syndrome · PPS

Data availability: 14 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant popliteal pterygium syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

14 retrieved; paginated sample, class counts are floors:

3 pathogenic/likely pathogenic, 3 benign, 3 uncertain significance, 2 pathogenic, 2 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
217873	NM_006147.4(IRF6):c.1210G>A (p.Glu404Lys)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265199	NM_006147.4(IRF6):c.859C>T (p.Gln287Ter)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382711	NM_006147.4(IRF6):c.1072del (p.His358fs)	IRF6	Pathogenic	criteria provided, single submitter
3414	NM_006147.4(IRF6):c.250C>T (p.Arg84Cys)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3415	NM_006147.4(IRF6):c.251G>A (p.Arg84His)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
3383146	NM_006147.4(IRF6):c.827T>C (p.Phe276Ser)	IRF6	Likely pathogenic	criteria provided, single submitter
976856	NM_006147.4(IRF6):c.194G>A (p.Gly65Glu)	IRF6	Likely pathogenic	criteria provided, single submitter
3421	NM_006147.4(IRF6):c.134G>A (p.Arg45Gln)	IRF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3382882	NM_006147.4(IRF6):c.586G>C (p.Glu196Gln)	IRF6	Uncertain significance	criteria provided, single submitter
3578419	NM_006147.4(IRF6):c.1385C>T (p.Pro462Leu)	IRF6	Uncertain significance	criteria provided, single submitter
4796578	NM_006147.4(IRF6):c.758A>T (p.Tyr253Phe)	IRF6	Uncertain significance	criteria provided, single submitter
259923	NM_006147.4(IRF6):c.175-5C>G	IRF6	Benign	criteria provided, multiple submitters, no conflicts
259925	NM_006147.4(IRF6):c.459G>T (p.Ser153=)	IRF6	Benign	criteria provided, multiple submitters, no conflicts
259926	NM_006147.4(IRF6):c.667+27C>G	IRF6	Benign	criteria provided, multiple submitters, no conflicts

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.