Branchiooculofacial syndrome

Summary

Branchiooculofacial syndrome (MONDO:0007235) is a disease caused by TFAP2A (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TFAP2A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 87
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Very frequent (80-99%)
HP:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0000589	Coloboma	Very frequent (80-99%)
HP:0000987	Atypical scarring of skin	Very frequent (80-99%)
HP:0001028	Hemangioma	Very frequent (80-99%)
HP:0002002	Deep philtrum	Very frequent (80-99%)
HP:0004464	Postauricular pit	Very frequent (80-99%)
HP:0004467	Preauricular pit	Very frequent (80-99%)
HP:0008606	Supraauricular pit	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000579	Nasolacrimal duct obstruction	Frequent (30-79%)
HP:0000582	Upslanted palpebral fissure	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0000691	Microdontia	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002216	Premature graying of hair	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0009804	Tooth agenesis	Frequent (30-79%)
HP:0100335	Non-midline cleft of the upper lip	Frequent (30-79%)
HP:0100798	Fingernail dysplasia	Frequent (30-79%)
HP:0000003	Multicystic kidney dysplasia	Occasional (5-29%)
HP:0000104	Renal agenesis	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001177	Preaxial hand polydactyly	Occasional (5-29%)
HP:0100268	Upper lip pit	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	branchiooculofacial syndrome
Mondo ID	MONDO:0007235
OMIM	113620
Orphanet	1297
DOID	DOID:0050691
SNOMED CT	449821007
UMLS	C0376524
MedGen	91261
GARD	0003212
NORD	871
Is cancer (heuristic)	no

Also known as: Bof syndrome · BOFS · BOFS syndrome · branchial clefts with characteristic facies growth retardation imperforate nasolacrimal duct and premature ageing · branchial clefts with characteristic facies growth retardation imperforate nasolacrimal duct and premature aging · branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, and premature Ageing · branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, and premature Aging · Branchio Oculo Facial Syndrome · branchio-oculo-facial syndrome · branchiooculofacial syndrome · hemangiomatous branchial clefts-Lip Pseudocleft syndrome · lip Pseudocleft-Hemangiomatous branchial cyst syndrome

Data availability: 87 ClinVar variants · 4 GenCC gene-disease records.

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 › branchiooculofacial 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, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, 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

87 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 22 likely pathogenic, 16 pathogenic, 10 likely benign, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
7935	NM_000503.6(EYA1):c.1319G>A (p.Arg440Gln)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17937	NM_001372066.1(TFAP2A):c.769A>G (p.Arg257Gly)	LOC121740638	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
192351	NM_001372066.1(TFAP2A):c.647T>A (p.Val216Asp)	LOC121740638	Pathogenic	criteria provided, single submitter
2431194	NM_001372066.1(TFAP2A):c.705A>C (p.Glu235Asp)	LOC121740638	Pathogenic	criteria provided, single submitter
522084	NM_001372066.1(TFAP2A):c.767G>A (p.Arg256Gln)	LOC121740638	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
547801	NM_001372066.1(TFAP2A):c.766C>G (p.Arg256Gly)	LOC121740638	Pathogenic	criteria provided, single submitter
547802	NM_001372066.1(TFAP2A):c.766C>T (p.Arg256Trp)	LOC121740638	Pathogenic	criteria provided, multiple submitters, no conflicts
17938	NM_001372066.1(TFAP2A):c.791G>A (p.Gly264Glu)	TFAP2A	Pathogenic	criteria provided, single submitter
17939	NM_001372066.1(TFAP2A):c.703_714del (p.Glu235_Arg238del)	TFAP2A	Pathogenic	no assertion criteria provided
17941	NM_001372066.1(TFAP2A):c.832_848delinsAGGAT (p.Leu278_Arg283delinsArgIle)	TFAP2A	Pathogenic	no assertion criteria provided
1805436	NM_001372066.1(TFAP2A):c.481del (p.Val161fs)	TFAP2A	Pathogenic	criteria provided, single submitter
18465	NM_001372066.1(TFAP2A):c.892G>A (p.Glu298Lys)	TFAP2A	Pathogenic	no assertion criteria provided
18466	NM_001372066.1(TFAP2A):c.716G>A (p.Arg239Gln)	TFAP2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582683	NM_001372066.1(TFAP2A):c.835_836del (p.Pro279fs)	TFAP2A	Pathogenic	criteria provided, single submitter
2844077	NM_001372066.1(TFAP2A):c.973C>T (p.Arg325Ter)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
4685488	Single allele	TFAP2A	Pathogenic	criteria provided, single submitter
523459	NM_001372066.1(TFAP2A):c.1043_1044del (p.Lys348fs)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
547798	NM_001372066.1(TFAP2A):c.716G>C (p.Arg239Pro)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
547803	NM_001372066.1(TFAP2A):c.773C>T (p.Ala258Val)	TFAP2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807514	NM_001372066.1(TFAP2A):c.752T>C (p.Leu251Pro)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
192350	NM_001372066.1(TFAP2A):c.655C>A (p.Arg219Ser)	TFAP2A-AS2	Pathogenic	criteria provided, single submitter
1344642	NM_000503.6(EYA1):c.966+1G>C	EYA1	Likely pathogenic	no assertion criteria provided
1679402	NM_001372066.1(TFAP2A):c.739A>G (p.Asn247Asp)	LOC121740638	Likely pathogenic	criteria provided, single submitter
1698731	NM_001372066.1(TFAP2A):c.687C>G (p.Tyr229Ter)	LOC121740638	Likely pathogenic	criteria provided, single submitter
3068210	NM_001372066.1(TFAP2A):c.639C>G (p.Phe213Leu)	LOC121740638	Likely pathogenic	criteria provided, single submitter
547799	NM_001372066.1(TFAP2A):c.719T>C (p.Leu240Pro)	LOC121740638	Likely pathogenic	criteria provided, single submitter
547800	NM_001372066.1(TFAP2A):c.755G>A (p.Gly252Asp)	LOC121740638	Likely pathogenic	criteria provided, single submitter
559909	NM_001372066.1(TFAP2A):c.712C>T (p.Arg238Trp)	LOC121740638	Likely pathogenic	criteria provided, single submitter
829802	NM_001372066.1(TFAP2A):c.758G>A (p.Gly253Glu)	LOC121740638	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028093	NM_001372066.1(TFAP2A):c.94C>T (p.Gln32Ter)	TFAP2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
TFAP2A	Definitive	Autosomal dominant	branchiooculofacial syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFAP2A	Orphanet:1297	Branchio-oculo-facial syndrome
EYA1	Orphanet:107	BOR syndrome
EYA1	Orphanet:2792	Otofaciocervical syndrome
EYA1	Orphanet:52429	Branchiootic syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TFAP2A	HGNC:11742	ENSG00000137203	P05549	Transcription factor AP-2-alpha	gencc,clinvar
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	clinvar
TFAP2A-AS2	HGNC:52289	ENSG00000285278		TFAP2A antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFAP2A	Transcription factor AP-2-alpha	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
EYA1	Protein phosphatase EYA1	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFAP2A	Transcription factor	no		TF_AP2, TF_AP2_alpha_N, TF_AP2_C
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
TFAP2A-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	1
gingival epithelium	1
upper leg skin	1
choroid plexus epithelium	1
mucosa of paranasal sinus	1
urethra	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFAP2A	220	ubiquitous	marker	upper leg skin, gingival epithelium, gingiva
EYA1	205	broad	marker	choroid plexus epithelium, urethra, mucosa of paranasal sinus
TFAP2A-AS2	112	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFAP2A	2,734
EYA1	1,806
TFAP2A-AS2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFAP2A	P05549	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EYA1	Q99502	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	1427.5×	0.006	TFAP2A
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	1142.0×	0.006	TFAP2A
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	1142.0×	0.006	TFAP2A
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	571.0×	0.007	TFAP2A
Activation of the TFAP2 (AP-2) family of transcription factors	1	475.8×	0.007	TFAP2A
Positive Regulation of CDH1 Gene Transcription	1	475.8×	0.007	TFAP2A
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	380.7×	0.007	TFAP2A
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.007	TFAP2A
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	317.2×	0.007	TFAP2A
Specification of the neural plate border	1	317.2×	0.007	TFAP2A
SUMOylation of transcription factors	1	285.5×	0.007	TFAP2A
Formation of the ureteric bud	1	248.3×	0.007	EYA1
Regulation of MITF-M-dependent genes involved in pigmentation	1	132.8×	0.012	TFAP2A
Gastrulation	1	129.8×	0.012	TFAP2A
MITF-M-dependent gene expression	1	90.6×	0.015	TFAP2A
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.018	EYA1
MITF-M-regulated melanocyte development	1	57.1×	0.022	TFAP2A
RNA Polymerase II Transcription	1	11.3×	0.101	TFAP2A
Gene expression (Transcription)	1	8.9×	0.120	TFAP2A
Generic Transcription Pathway	1	7.5×	0.134	TFAP2A
Developmental Biology	1	7.2×	0.134	TFAP2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
optic cup structural organization	1	8426.0×	0.002	TFAP2A
otic vesicle morphogenesis	1	8426.0×	0.002	EYA1
sensory perception of sound	2	100.9×	0.002	TFAP2A, EYA1
optic vesicle morphogenesis	1	4213.0×	0.003	TFAP2A
oculomotor nerve formation	1	4213.0×	0.003	TFAP2A
positive regulation of tooth mineralization	1	2808.7×	0.003	TFAP2A
positive regulation of secondary heart field cardioblast proliferation	1	2808.7×	0.003	EYA1
striated muscle tissue development	1	2106.5×	0.003	EYA1
trigeminal nerve development	1	1203.7×	0.004	TFAP2A
semicircular canal morphogenesis	1	1203.7×	0.004	EYA1
cellular response to iron ion	1	1203.7×	0.004	TFAP2A
mesodermal cell fate specification	1	1053.2×	0.005	EYA1
outer ear morphogenesis	1	766.0×	0.006	EYA1
obsolete negative regulation of transcription by competitive promoter binding	1	648.1×	0.006	TFAP2A
eyelid development in camera-type eye	1	526.6×	0.007	TFAP2A
negative regulation of reactive oxygen species metabolic process	1	468.1×	0.008	TFAP2A
aorta morphogenesis	1	443.5×	0.008	EYA1
pharyngeal system development	1	401.2×	0.008	EYA1
regulation of neuron differentiation	1	366.4×	0.008	EYA1
middle ear morphogenesis	1	351.1×	0.008	EYA1
neuron fate specification	1	351.1×	0.008	EYA1
retina layer formation	1	324.1×	0.008	TFAP2A
bone morphogenesis	1	300.9×	0.008	TFAP2A
embryonic cranial skeleton morphogenesis	1	290.6×	0.008	TFAP2A
cochlea morphogenesis	1	290.6×	0.008	EYA1
metanephros development	1	255.3×	0.008	EYA1
embryonic forelimb morphogenesis	1	247.8×	0.008	TFAP2A
pattern specification process	1	234.1×	0.008	EYA1
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.008	EYA1
regulation of cell differentiation	1	216.1×	0.008	TFAP2A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TFAP2A	0	0
EYA1	0	0
TFAP2A-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	TFAP2A, EYA1, TFAP2A-AS2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TFAP2A	0	—
EYA1	0	—
TFAP2A-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.