Branchiootorenal syndrome 1

Summary

Branchiootorenal syndrome 1 (MONDO:0007236) is a disease caused by EYA1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: EYA1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 195

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	branchiootorenal syndrome 1
Mondo ID	MONDO:0007236
OMIM	113650
DOID	DOID:0111423
UMLS	C4551702
MedGen	1632634
GARD	0024535
Is cancer (heuristic)	no

Also known as: BOR1 · branchiootorenal syndrome 1 · branchiootorenal syndrome 1, with or without cataracts · branchiootorenal syndrome type 1

Data availability: 195 ClinVar variants · 2 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 › branchio-oto-renal syndrome › branchiootorenal syndrome 1

Related subtypes (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

195 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 40 pathogenic, 32 likely pathogenic, 23 conflicting classifications of pathogenicity, 13 benign/likely benign, 9 likely benign, 6 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069048	NM_000503.6(EYA1):c.1698+1G>T	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1448479	NM_000503.6(EYA1):c.775C>T (p.Gln259Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457237	NM_000503.6(EYA1):c.1051-2A>G	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1459746	NM_000503.6(EYA1):c.1487_1488del (p.Val496fs)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
163427	NM_000503.6(EYA1):c.1475+1G>C	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2429116	NM_000503.6(EYA1):c.1611T>A (p.Cys537Ter)	EYA1	Pathogenic	criteria provided, single submitter
2442143	NM_000503.6(EYA1):c.981G>A (p.Trp327Ter)	EYA1	Pathogenic	criteria provided, single submitter
3377161	NM_000503.6(EYA1):c.912del (p.Gly305fs)	EYA1	Pathogenic	criteria provided, single submitter
3595826	NM_000503.6(EYA1):c.1510C>T (p.Gln504Ter)	EYA1	Pathogenic	criteria provided, single submitter
3601092	NM_000503.6(EYA1):c.1123_1129del (p.Phe375fs)	EYA1	Pathogenic	criteria provided, single submitter
3601095	NM_000503.6(EYA1):c.1200-1G>C	EYA1	Pathogenic	criteria provided, single submitter
3601096	NM_000503.6(EYA1):c.1335C>A (p.Tyr445Ter)	EYA1	Pathogenic	criteria provided, single submitter
3601097	NM_000503.6(EYA1):c.1360+1G>A	EYA1	Pathogenic	criteria provided, single submitter
3601099	NM_000503.6(EYA1):c.1474del (p.Arg492fs)	EYA1	Pathogenic	criteria provided, single submitter
3601106	NM_000503.6(EYA1):c.1715G>A (p.Trp572Ter)	EYA1	Pathogenic	criteria provided, single submitter
3601112	NM_000503.6(EYA1):c.632C>A (p.Ser211Ter)	EYA1	Pathogenic	criteria provided, single submitter
3601115	NM_000503.6(EYA1):c.972del (p.Phe325fs)	EYA1	Pathogenic	criteria provided, single submitter
4072061	NM_000503.6(EYA1):c.1199+1G>A	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429912	NM_000503.6(EYA1):c.889C>T (p.Arg297Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4532103	NM_000503.6(EYA1):c.671del (p.Gly224fs)	EYA1	Pathogenic	criteria provided, single submitter
459254	NM_000503.6(EYA1):c.229C>T (p.Arg77Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813663	NM_000503.6(EYA1):c.1391G>A (p.Trp464Ter)	EYA1	Pathogenic	criteria provided, single submitter
522400	NM_000503.6(EYA1):c.1044T>G (p.Tyr348Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
528878	NC_000008.11:g.(?71244583)(71322288_?)del	EYA1	Pathogenic	criteria provided, single submitter
562334	NM_000503.6(EYA1):c.1597+1G>A	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
567492	NM_000503.6(EYA1):c.682C>T (p.Gln228Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
584228	NC_000008.11:g.(?71199320)(71356506_?)del	EYA1	Pathogenic	criteria provided, single submitter
7929	NM_000503.6(EYA1):c.922C>T (p.Arg308Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
7930	NM_000503.6(EYA1):c.1350delinsCC (p.Asn451fs)	EYA1	Pathogenic	no assertion criteria provided
7933	NG_011735.4:g.308479_308480insAlu308464_308481dup	EYA1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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	branchiootorenal syndrome 1	6

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

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	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

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

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

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

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

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIX1	1,977
EYA1	1,806

Intra-cohort edges

A	B	Sources
EYA1	SIX1	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SIX1	Q15475	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EYA1	Q99502	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Formation of the ureteric bud	2	496.5×	2e-05	EYA1, SIX1
Kidney development	1	407.9×	0.005	SIX1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.018	EYA1
Developmental Biology	1	7.2×	0.134	SIX1

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
positive regulation of secondary heart field cardioblast proliferation	2	5617.3×	2e-06	EYA1, SIX1
aorta morphogenesis	2	887.0×	2e-05	EYA1, SIX1
pharyngeal system development	2	802.5×	2e-05	EYA1, SIX1
regulation of neuron differentiation	2	732.7×	2e-05	EYA1, SIX1
middle ear morphogenesis	2	702.2×	2e-05	EYA1, SIX1
neuron fate specification	2	702.2×	2e-05	EYA1, SIX1
cochlea morphogenesis	2	581.1×	3e-05	EYA1, SIX1
pattern specification process	2	468.1×	4e-05	EYA1, SIX1
embryonic skeletal system morphogenesis	2	391.9×	5e-05	EYA1, SIX1
branching involved in ureteric bud morphogenesis	2	366.4×	6e-05	EYA1, SIX1
outflow tract morphogenesis	2	306.4×	7e-05	EYA1, SIX1
otic vesicle morphogenesis	1	8426.0×	6e-04	EYA1
mesonephric tubule formation	1	8426.0×	6e-04	SIX1
mesenchymal cell proliferation involved in ureter development	1	8426.0×	6e-04	SIX1
sensory perception of sound	2	100.9×	6e-04	EYA1, SIX1
regulation of skeletal muscle cell proliferation	1	4213.0×	9e-04	SIX1
facial nerve morphogenesis	1	4213.0×	9e-04	SIX1
fungiform papilla morphogenesis	1	4213.0×	9e-04	SIX1
cellular response to 3,3’,5-triiodo-L-thyronine	1	4213.0×	9e-04	SIX1
positive regulation of mesenchymal cell proliferation involved in ureter development	1	4213.0×	9e-04	SIX1
olfactory placode formation	1	2808.7×	0.001	SIX1
regulation of branch elongation involved in ureteric bud branching	1	2808.7×	0.001	SIX1
ureter smooth muscle cell differentiation	1	2808.7×	0.001	SIX1
striated muscle tissue development	1	2106.5×	0.001	EYA1
myotome development	1	2106.5×	0.001	SIX1
trigeminal ganglion development	1	2106.5×	0.001	SIX1
regulation of skeletal muscle satellite cell proliferation	1	1404.3×	0.002	SIX1
otic vesicle development	1	1404.3×	0.002	SIX1
positive regulation of ureteric bud formation	1	1404.3×	0.002	SIX1
regulation of skeletal muscle cell differentiation	1	1404.3×	0.002	SIX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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

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: 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	2	EYA1, SIX1

Undrugged target profiles

2 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	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.