Branchiootic syndrome 1

Summary

Branchiootic syndrome 1 (MONDO:0011258) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 218

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	branchiootic syndrome 1
Mondo ID	MONDO:0011258
OMIM	602588
DOID	DOID:0061209
UMLS	C1865143
MedGen	351307
GARD	0024783
Is cancer (heuristic)	no

Also known as: BOS1 · branchiootic syndrome 1 · branchiootic syndrome caused by mutation in EYA1 · branchiootic syndrome type 1 · EYA1 branchiootic syndrome

Data availability: 218 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › branchiootic syndrome › branchiootic syndrome 1

Related subtypes (2): branchiootic syndrome 2, branchiootic syndrome 3

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

218 retrieved; paginated sample, class counts are floors:

97 uncertain significance, 30 conflicting classifications of pathogenicity, 26 benign, 20 pathogenic, 20 benign/likely benign, 11 likely pathogenic, 10 likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069545	NM_000503.6(EYA1):c.637C>T (p.Gln213Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1202644	NM_000503.6(EYA1):c.1425del (p.Asp476fs)	EYA1	Pathogenic	criteria provided, single submitter
1202645	NM_000503.6(EYA1):c.1140+1G>A	EYA1	Pathogenic	criteria provided, single submitter
1297081	NM_000503.6(EYA1):c.639+2T>G	EYA1	Pathogenic	no assertion criteria provided
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
2580901	NM_000503.6(EYA1):c.1408G>T (p.Glu470Ter)	EYA1	Pathogenic	criteria provided, single submitter
2664718	NM_000503.6(EYA1):c.1598-2del	EYA1	Pathogenic	criteria provided, single submitter
2681781	NM_000503.6(EYA1):c.1545T>G (p.Tyr515Ter)	EYA1	Pathogenic	criteria provided, single submitter
3340777	NM_000503.6(EYA1):c.1254_1255del (p.Cys419fs)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
3595826	NM_000503.6(EYA1):c.1510C>T (p.Gln504Ter)	EYA1	Pathogenic	criteria provided, single submitter
4070999	NM_000503.6(EYA1):c.639+98_760del	EYA1	Pathogenic	no assertion criteria provided
429912	NM_000503.6(EYA1):c.889C>T (p.Arg297Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
459254	NM_000503.6(EYA1):c.229C>T (p.Arg77Ter)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562334	NM_000503.6(EYA1):c.1597+1G>A	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7929	NM_000503.6(EYA1):c.922C>T (p.Arg308Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
7931	NM_000503.6(EYA1):c.972_973dup (p.Phe325fs)	EYA1	Pathogenic	no assertion criteria provided
7932	NM_000503.6(EYA1):c.398_405del (p.Pro133fs)	EYA1	Pathogenic	no assertion criteria provided
7935	NM_000503.6(EYA1):c.1319G>A (p.Arg440Gln)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7943	NM_000503.6(EYA1):c.1081C>T (p.Arg361Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
7944	NM_000503.6(EYA1):c.1501_1507del (p.Thr501fs)	EYA1	Pathogenic	no assertion criteria provided
807413	NM_000503.6(EYA1):c.1361-1G>A	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
854287	NM_000503.6(EYA1):c.1050+1G>T	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4814013	NM_000335.5(SCN5A):c.4507_4515del (p.Lys1503_Pro1505del)	SCN5A	Pathogenic	no assertion criteria provided
1691281	NM_000503.6(EYA1):c.1650_1651dup (p.Tyr551fs)	EYA1	Likely pathogenic	criteria provided, single submitter
2671884	NM_000503.6(EYA1):c.639+3A>C	EYA1	Likely pathogenic	criteria provided, single submitter
3383944	NM_000503.6(EYA1):c.1286A>G (p.Asp429Gly)	EYA1	Likely pathogenic	no assertion criteria provided
3595827	NM_000503.6(EYA1):c.1496T>G (p.Leu499Ter)	EYA1	Likely pathogenic	criteria provided, single submitter
3595828	NM_000503.6(EYA1):c.1361-2A>C	EYA1	Likely pathogenic	criteria provided, single submitter
3595831	NM_000503.6(EYA1):c.1277dup (p.Gly427fs)	EYA1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
EYA1	Orphanet:107	BOR syndrome
EYA1	Orphanet:2792	Otofaciocervical syndrome
EYA1	Orphanet:52429	Branchiootic syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	clinvar
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
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: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.080
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
biceps brachii	1
parotid gland	1
skeletal muscle tissue of biceps brachii	1
choroid plexus epithelium	1
mucosa of paranasal sinus	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
EYA1	205	broad	marker	choroid plexus epithelium, urethra, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN5A	2,090
SIX1	1,977
EYA1	1,806

Intra-cohort edges

A	B	Sources
EYA1	SIX1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16
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: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 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	331.0×	1e-04	SIX1, EYA1
Kidney development	1	271.9×	0.020	SIX1
Interaction between L1 and Ankyrins	1	122.8×	0.024	SCN5A
Phase 0 - rapid depolarisation	1	115.3×	0.024	SCN5A
Developmental Biology	2	9.6×	0.030	SCN5A, SIX1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	48.8×	0.037	EYA1
L1CAM interactions	1	40.1×	0.038	SCN5A
Cardiac conduction	1	36.2×	0.038	SCN5A
Muscle contraction	1	25.7×	0.047	SCN5A
Axon guidance	1	15.1×	0.068	SCN5A
Nervous system development	1	14.3×	0.068	SCN5A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	3744.9×	7e-06	SIX1, EYA1
aorta morphogenesis	2	591.3×	1e-04	SIX1, EYA1
pharyngeal system development	2	535.0×	1e-04	SIX1, EYA1
regulation of neuron differentiation	2	488.5×	1e-04	SIX1, EYA1
middle ear morphogenesis	2	468.1×	1e-04	SIX1, EYA1
neuron fate specification	2	468.1×	1e-04	SIX1, EYA1
cochlea morphogenesis	2	387.4×	1e-04	SIX1, EYA1
pattern specification process	2	312.1×	2e-04	SIX1, EYA1
embryonic skeletal system morphogenesis	2	261.3×	2e-04	SIX1, EYA1
branching involved in ureteric bud morphogenesis	2	244.2×	2e-04	SIX1, EYA1
outflow tract morphogenesis	2	204.3×	3e-04	SIX1, EYA1
positive regulation of epithelial cell proliferation	2	162.8×	5e-04	SCN5A, EYA1
otic vesicle morphogenesis	1	5617.3×	0.001	EYA1
mesonephric tubule formation	1	5617.3×	0.001	SIX1
mesenchymal cell proliferation involved in ureter development	1	5617.3×	0.001	SIX1
regulation of skeletal muscle cell proliferation	1	2808.7×	0.002	SIX1
facial nerve morphogenesis	1	2808.7×	0.002	SIX1
fungiform papilla morphogenesis	1	2808.7×	0.002	SIX1
bundle of His cell action potential	1	2808.7×	0.002	SCN5A
AV node cell to bundle of His cell communication	1	2808.7×	0.002	SCN5A
cellular response to 3,3’,5-triiodo-L-thyronine	1	2808.7×	0.002	SIX1
positive regulation of mesenchymal cell proliferation involved in ureter development	1	2808.7×	0.002	SIX1
sensory perception of sound	2	67.3×	0.002	SIX1, EYA1
olfactory placode formation	1	1872.4×	0.002	SIX1
regulation of branch elongation involved in ureteric bud branching	1	1872.4×	0.002	SIX1
ureter smooth muscle cell differentiation	1	1872.4×	0.002	SIX1
membrane depolarization during Purkinje myocyte cell action potential	1	1872.4×	0.002	SCN5A
membrane depolarization during bundle of His cell action potential	1	1872.4×	0.002	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	1872.4×	0.002	SCN5A
striated muscle tissue development	1	1404.3×	0.002	EYA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
SIX1	0	0
EYA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
SIX1	12	Binding:12

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN5A	594

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN5A
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	SIX1, EYA1

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)
SIX1	12	—
EYA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.