Branchio-oto-renal syndrome

Summary

Branchio-oto-renal syndrome (MONDO:0007029) is a disease caused by variants in EYA1 and SIX1, with 7 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal genes: EYA1 (GenCC Definitive), SIX1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 341
• Phenotypes (HPO): 38

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.5	Worldwide	Validated
Point prevalence	1-9 / 100 000	2.5	Canada	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000359	Abnormality of the inner ear	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000370	Abnormality of the middle ear	Very frequent (80-99%)
HP:0004467	Preauricular pit	Very frequent (80-99%)
HP:0000384	Preauricular skin tag	Frequent (30-79%)
HP:0000394	Lop ear	Frequent (30-79%)
HP:0000402	Stenosis of the external auditory canal	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000410	Mixed hearing impairment	Frequent (30-79%)
HP:0000413	Atresia of the external auditory canal	Frequent (30-79%)
HP:0004452	Abnormality of the middle ear ossicles	Frequent (30-79%)
HP:0008586	Hypoplasia of the cochlea	Frequent (30-79%)
HP:0008678	Renal hypoplasia/aplasia	Frequent (30-79%)
HP:0009794	Branchial anomaly	Frequent (30-79%)
HP:0009796	Branchial cyst	Frequent (30-79%)
HP:0011387	Enlarged vestibular aqueduct	Frequent (30-79%)
HP:0011388	Enlarged cochlear aqueduct	Frequent (30-79%)
HP:0011395	Aplasia/Hypoplasia of the cochlea	Frequent (30-79%)
HP:0100272	Branchial sinus	Frequent (30-79%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000003	Multicystic kidney dysplasia	Occasional (5-29%)
HP:0000074	Ureteropelvic junction obstruction	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000356	Abnormality of the outer ear	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0007925	Lacrimal duct aplasia	Occasional (5-29%)
HP:0008551	Microtia	Occasional (5-29%)
HP:0009798	Euthyroid goiter	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0011481	Abnormal lacrimal duct morphology	Occasional (5-29%)
HP:0040106	Morphological abnormality of the lateral semicircular canal	Occasional (5-29%)
HP:0100274	Gustatory lacrimation	Occasional (5-29%)
HP:0100581	Dilatation of renal calices	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	branchio-oto-renal syndrome
Mondo ID	MONDO:0007029
MeSH	D019280
OMIM	113650
Orphanet	107
DOID	DOID:14702
ICD-11	504227287
NCIT	C98983
SNOMED CT	290006
UMLS	C0265234
MedGen	82693
GARD	0010147
MedDRA	10071135
Is cancer (heuristic)	no

Also known as: Branchio oto renal syndrome · Branchio-Oto-renal syndrome · branchio-oto-renal syndrome · branchiootorenal syndrome · Melnick-Fraser syndrome

Data availability: 341 ClinVar variants · 8 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › branchio-oto-renal 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, 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, 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

Subtypes (2): branchiootorenal syndrome 1, branchiootorenal 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

341 retrieved; paginated sample, class counts are floors:

91 uncertain significance, 85 likely benign, 73 pathogenic, 36 conflicting classifications of pathogenicity, 18 benign/likely benign, 14 pathogenic/likely pathogenic, 12 likely pathogenic, 12 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069048	NM_000503.6(EYA1):c.1698+1G>T	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069049	NM_000503.6(EYA1):c.1644del (p.Val549fs)	EYA1	Pathogenic	criteria provided, single submitter
1069545	NM_000503.6(EYA1):c.637C>T (p.Gln213Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072507	NM_000503.6(EYA1):c.1476-2A>T	EYA1	Pathogenic	criteria provided, single submitter
1370990	NM_000503.6(EYA1):c.1315del (p.Arg439fs)	EYA1	Pathogenic	criteria provided, single submitter
1391097	NM_000503.6(EYA1):c.1619_1620del (p.Arg540fs)	EYA1	Pathogenic	criteria provided, single submitter
1422984	NM_000503.6(EYA1):c.1272dup (p.Arg425fs)	EYA1	Pathogenic	criteria provided, single submitter
1428718	NM_000503.6(EYA1):c.782del (p.Pro261fs)	EYA1	Pathogenic	criteria provided, single submitter
1433497	NM_000503.6(EYA1):c.355C>T (p.Gln119Ter)	EYA1	Pathogenic	criteria provided, single submitter
1448479	NM_000503.6(EYA1):c.775C>T (p.Gln259Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452496	NC_000008.10:g.(?72111575)(72267140_?)del	EYA1	Pathogenic	criteria provided, single submitter
1453510	NM_000503.6(EYA1):c.490dup (p.Leu164fs)	EYA1	Pathogenic	criteria provided, single submitter
1455041	NM_000503.6(EYA1):c.1182dup (p.Asn395Ter)	EYA1	Pathogenic	criteria provided, single submitter
1457237	NM_000503.6(EYA1):c.1051-2A>G	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457573	NC_000008.10:g.(?72123371)(72123511_?)del	EYA1	Pathogenic	criteria provided, single submitter
1457990	NM_000503.6(EYA1):c.1325_1326del (p.Lys442fs)	EYA1	Pathogenic	criteria provided, single submitter
1458401	NM_000503.6(EYA1):c.1236dup (p.Ala413fs)	EYA1	Pathogenic	criteria provided, single submitter
1459746	NM_000503.6(EYA1):c.1487_1488del (p.Val496fs)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1460082	NM_000503.6(EYA1):c.654T>G (p.Tyr218Ter)	EYA1	Pathogenic	criteria provided, single submitter
1698351	NM_000503.6(EYA1):c.1189C>T (p.Gln397Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1998220	NM_000503.6(EYA1):c.1248dup (p.Asn417Ter)	EYA1	Pathogenic	criteria provided, single submitter
2016093	NM_000503.6(EYA1):c.1050+4A>G	EYA1	Pathogenic	criteria provided, single submitter
2022135	NM_000503.6(EYA1):c.1570_1571insTA (p.Glu524fs)	EYA1	Pathogenic	criteria provided, single submitter
2022136	NM_000503.6(EYA1):c.1545T>A (p.Tyr515Ter)	EYA1	Pathogenic	criteria provided, single submitter
2026323	NM_000503.6(EYA1):c.1084del (p.Met362fs)	EYA1	Pathogenic	criteria provided, single submitter
2028798	NM_000503.6(EYA1):c.402C>G (p.Tyr134Ter)	EYA1	Pathogenic	criteria provided, single submitter
2064338	NM_000503.6(EYA1):c.1598-1G>C	EYA1	Pathogenic	criteria provided, single submitter
2111414	NM_000503.6(EYA1):c.950del (p.Pro317fs)	EYA1	Pathogenic	criteria provided, single submitter
2136678	NM_000503.6(EYA1):c.1627C>T (p.Gln543Ter)	EYA1	Pathogenic	criteria provided, single submitter
2136681	NM_000503.6(EYA1):c.678C>G (p.Tyr226Ter)	EYA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 13 · 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
EYA1	Definitive	Autosomal dominant	branchio-oto-renal syndrome	6
SIX1	Definitive	Autosomal dominant	branchio-oto-renal syndrome	10
SIX5	Supportive	Autosomal dominant	branchio-oto-renal syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EYA1	Orphanet:107	BOR syndrome
EYA1	Orphanet:2792	Otofaciocervical syndrome
EYA1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
SIX5	Orphanet:107	BOR syndrome
TFAP2A	Orphanet:1297	Branchio-oculo-facial syndrome
TJP2	Orphanet:238475	Familial hypercholanemia
TJP2	Orphanet:480483	Progressive familial intrahepatic cholestasis type 4
TJP2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CLRN1	Orphanet:231183	Usher syndrome type 3
CLRN1	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	gencc,clinvar
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	gencc
SIX5	HGNC:10891	ENSG00000177045	Q8N196	Homeobox protein SIX5	gencc
TFAP2A	HGNC:11742	ENSG00000137203	P05549	Transcription factor AP-2-alpha	clinvar
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	clinvar
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	clinvar
MIR9718	HGNC:53988			microRNA 9718	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EYA1	Protein phosphatase EYA1	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
SIX5	Homeobox protein SIX5	Transcription factor that is thought to be involved in regulation of organogenesis.
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.
TJP2	Tight junction protein 2	Plays a role in tight junctions and adherens junctions.
CLRN1	Clarin-1	May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.

Protein-family classification

Druggable: 0 · Difficult: 4 · Unknown: 3 · 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	3.5×	0.128
Scaffold/PPI	1	2.5×	0.512
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
SIX5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TFAP2A	Transcription factor	no		TF_AP2, TF_AP2_alpha_N, TF_AP2_C
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
CLRN1	Other/Unknown	no		Clarin
MIR9718	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

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	1

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
mucosa of paranasal sinus	1
urethra	1
biceps brachii	1
parotid gland	1
skeletal muscle tissue of biceps brachii	1
cardiac muscle of right atrium	1
right ovary	1
right uterine tube	1
gingiva	1
gingival epithelium	1
upper leg skin	1
corpus callosum	1
descending thoracic aorta	1
thoracic aorta	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EYA1	205	broad	marker	choroid plexus epithelium, urethra, mucosa of paranasal sinus
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
SIX5	205	ubiquitous	yes	cardiac muscle of right atrium, right uterine tube, right ovary
TFAP2A	220	ubiquitous	marker	upper leg skin, gingival epithelium, gingiva
TJP2	134	ubiquitous	marker	corpus callosum, descending thoracic aorta, thoracic aorta
CLRN1	61	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
MIR9718

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TJP2	2,916
TFAP2A	2,734
SIX1	1,977
EYA1	1,806
SIX5	1,158
CLRN1	727
MIR9718	0

Intra-cohort edges

A	B	Sources
EYA1	SIX1	biogrid_interaction, intact, string_interaction
EYA1	SIX5	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFAP2A	P05549	3
TJP2	Q9UDY2	2
SIX1	Q15475	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLRN1	P58418	90.74
EYA1	Q99502	66.68
SIX5	Q8N196	53.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 7 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
Formation of the ureteric bud	2	248.3×	6e-04	EYA1, SIX1
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	713.8×	0.012	TFAP2A
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	571.0×	0.012	TFAP2A
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	571.0×	0.012	TFAP2A
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	285.5×	0.013	TFAP2A
Apoptotic cleavage of cell adhesion proteins	1	259.6×	0.013	TJP2
Activation of the TFAP2 (AP-2) family of transcription factors	1	237.9×	0.013	TFAP2A
Positive Regulation of CDH1 Gene Transcription	1	237.9×	0.013	TFAP2A
Kidney development	1	203.9×	0.013	SIX1
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	190.3×	0.013	TFAP2A
Developmental Lineage of Mammary Stem Cells	1	190.3×	0.013	TFAP2A
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	158.6×	0.013	TFAP2A
Specification of the neural plate border	1	158.6×	0.013	TFAP2A
SUMOylation of transcription factors	1	142.8×	0.013	TFAP2A
Signaling by Hippo	1	135.9×	0.013	TJP2
Regulation of MITF-M-dependent genes involved in pigmentation	1	66.4×	0.024	TFAP2A
Gastrulation	1	64.9×	0.024	TFAP2A
MITF-M-dependent gene expression	1	45.3×	0.033	TFAP2A
RHOB GTPase cycle	1	38.6×	0.033	TJP2
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	36.6×	0.033	EYA1
RHOC GTPase cycle	1	36.6×	0.033	TJP2
Developmental Biology	2	7.2×	0.033	SIX1, TFAP2A
MITF-M-regulated melanocyte development	1	28.6×	0.041	TFAP2A
RHOA GTPase cycle	1	18.7×	0.059	TJP2
RNA Polymerase II Transcription	1	5.6×	0.179	TFAP2A
Gene expression (Transcription)	1	4.5×	0.214	TFAP2A
Generic Transcription Pathway	1	3.8×	0.240	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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of sound	4	67.3×	2e-05	EYA1, SIX1, TFAP2A, CLRN1
positive regulation of secondary heart field cardioblast proliferation	2	1872.4×	2e-05	EYA1, SIX1
aorta morphogenesis	2	295.6×	5e-04	EYA1, SIX1
pharyngeal system development	2	267.5×	5e-04	EYA1, SIX1
regulation of neuron differentiation	2	244.2×	5e-04	EYA1, SIX1
middle ear morphogenesis	2	234.1×	5e-04	EYA1, SIX1
neuron fate specification	2	234.1×	5e-04	EYA1, SIX1
embryonic cranial skeleton morphogenesis	2	193.7×	6e-04	SIX1, TFAP2A
cochlea morphogenesis	2	193.7×	6e-04	EYA1, SIX1
pattern specification process	2	156.0×	8e-04	EYA1, SIX1
embryonic skeletal system morphogenesis	2	130.6×	0.001	EYA1, SIX1
branching involved in ureteric bud morphogenesis	2	122.1×	0.001	EYA1, SIX1
outflow tract morphogenesis	2	102.1×	0.001	EYA1, SIX1
inner ear morphogenesis	2	100.3×	0.001	SIX1, TFAP2A
optic cup structural organization	1	2808.7×	0.002	TFAP2A
otic vesicle morphogenesis	1	2808.7×	0.002	EYA1
mesonephric tubule formation	1	2808.7×	0.002	SIX1
mesenchymal cell proliferation involved in ureter development	1	2808.7×	0.002	SIX1
optic vesicle morphogenesis	1	1404.3×	0.003	TFAP2A
regulation of skeletal muscle cell proliferation	1	1404.3×	0.003	SIX1
facial nerve morphogenesis	1	1404.3×	0.003	SIX1
oculomotor nerve formation	1	1404.3×	0.003	TFAP2A
fungiform papilla morphogenesis	1	1404.3×	0.003	SIX1
Leydig cell proliferation	1	1404.3×	0.003	SIX5
cellular response to 3,3’,5-triiodo-L-thyronine	1	1404.3×	0.003	SIX1
positive regulation of mesenchymal cell proliferation involved in ureter development	1	1404.3×	0.003	SIX1
kidney development	2	46.8×	0.003	SIX1, TFAP2A
olfactory placode formation	1	936.2×	0.004	SIX1
positive regulation of tooth mineralization	1	936.2×	0.004	TFAP2A
regulation of branch elongation involved in ureteric bud branching	1	936.2×	0.004	SIX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 1 of 7 evidence-associated genes (14%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EYA1	0	0
SIX1	0	0
SIX5	0	0
TFAP2A	0	0
TJP2	0	0
CLRN1	0	0
MIR9718	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SIX1	12	Binding:12

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

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	7	EYA1, SIX1, SIX5, TFAP2A, TJP2, CLRN1, MIR9718

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EYA1	0	—
SIX1	12	—
SIX5	0	—
TFAP2A	0	—
TJP2	0	—
CLRN1	0	—
MIR9718	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.