Otofaciocervical syndrome 1

Summary

Otofaciocervical syndrome 1 (MONDO:0024532) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 199

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	otofaciocervical syndrome 1
Mondo ID	MONDO:0024532
OMIM	166780
UMLS	C3714941
MedGen	811516
GARD	0016502
Is cancer (heuristic)	no

Also known as: EYA1 otofaciocervical syndrome · OFC · OFC1 · OTFCS · otofaciocervical syndrome · otofaciocervical syndrome 1 · otofaciocervical syndrome caused by mutation in EYA1

Data availability: 199 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › otofaciocervical syndrome › otofaciocervical syndrome 1

Related subtypes (1): otofaciocervical 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

199 retrieved; paginated sample, class counts are floors:

96 uncertain significance, 28 conflicting classifications of pathogenicity, 26 benign, 20 benign/likely benign, 11 likely benign, 8 likely pathogenic, 7 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
3595826	NM_000503.6(EYA1):c.1510C>T (p.Gln504Ter)	EYA1	Pathogenic	criteria provided, single submitter
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
7935	NM_000503.6(EYA1):c.1319G>A (p.Arg440Gln)	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7942	NM_000503.6(EYA1):c.639+1G>A	EYA1	Pathogenic	criteria provided, single submitter
7943	NM_000503.6(EYA1):c.1081C>T (p.Arg361Ter)	EYA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2498127	NM_000503.6(EYA1):c.1698+2T>C	EYA1	Likely pathogenic	criteria provided, single submitter
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
3595834	NM_000503.6(EYA1):c.1137del (p.Glu380fs)	EYA1	Likely pathogenic	criteria provided, single submitter
417930	NM_000503.6(EYA1):c.1615G>T (p.Glu539Ter)	EYA1	Likely pathogenic	no assertion criteria provided
4531236	NM_000503.6(EYA1):c.1538T>C (p.Leu513Pro)	EYA1	Likely pathogenic	criteria provided, single submitter
48106	NM_000503.6(EYA1):c.1748T>C (p.Leu583Pro)	EYA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1302627	NM_000503.6(EYA1):c.163A>G (p.Thr55Ala)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420334	NM_000503.6(EYA1):c.34C>T (p.Arg12Cys)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446417	NM_000503.6(EYA1):c.910C>T (p.Arg304Cys)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163440	NM_000503.6(EYA1):c.107C>T (p.Thr36Ile)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163441	NM_000503.6(EYA1):c.65G>A (p.Gly22Asp)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179232	NM_000503.6(EYA1):c.299C>A (p.Thr100Asn)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194813	NM_000503.6(EYA1):c.1699-8T>C	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2081341	NM_000503.6(EYA1):c.1309C>T (p.Arg437Cys)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2136680	NM_000503.6(EYA1):c.679G>A (p.Ala227Thr)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225350	NM_000503.6(EYA1):c.671G>T (p.Gly224Val)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225351	NM_000503.6(EYA1):c.403G>A (p.Gly135Ser)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
228678	NM_000503.6(EYA1):c.1460C>T (p.Ser487Leu)	EYA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

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
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	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.

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)
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_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
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
EYA1	205	broad	marker	choroid plexus epithelium, urethra, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EYA1	1,806

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EYA1	Q99502	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Formation of the ureteric bud	1	496.5×	0.004	EYA1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.007	EYA1

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
otic vesicle morphogenesis	1	16852.0×	0.002	EYA1
positive regulation of secondary heart field cardioblast proliferation	1	5617.3×	0.002	EYA1
striated muscle tissue development	1	4213.0×	0.002	EYA1
semicircular canal morphogenesis	1	2407.4×	0.003	EYA1
mesodermal cell fate specification	1	2106.5×	0.003	EYA1
outer ear morphogenesis	1	1532.0×	0.003	EYA1
aorta morphogenesis	1	887.0×	0.004	EYA1
pharyngeal system development	1	802.5×	0.004	EYA1
regulation of neuron differentiation	1	732.7×	0.004	EYA1
middle ear morphogenesis	1	702.2×	0.004	EYA1
neuron fate specification	1	702.2×	0.004	EYA1
cochlea morphogenesis	1	581.1×	0.004	EYA1
metanephros development	1	510.7×	0.004	EYA1
pattern specification process	1	468.1×	0.004	EYA1
extrinsic apoptotic signaling pathway in absence of ligand	1	468.1×	0.004	EYA1
response to ionizing radiation	1	411.0×	0.004	EYA1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	411.0×	0.004	EYA1
embryonic skeletal system morphogenesis	1	391.9×	0.004	EYA1
branching involved in ureteric bud morphogenesis	1	366.4×	0.004	EYA1
positive regulation of DNA repair	1	358.6×	0.004	EYA1
protein sumoylation	1	324.1×	0.004	EYA1
epithelial cell proliferation	1	312.1×	0.004	EYA1
outflow tract morphogenesis	1	306.4×	0.004	EYA1
positive regulation of epithelial cell proliferation	1	244.2×	0.005	EYA1
double-strand break repair	1	203.0×	0.006	EYA1
anatomical structure morphogenesis	1	139.3×	0.008	EYA1
sensory perception of sound	1	100.9×	0.011	EYA1
cell differentiation	1	29.1×	0.036	EYA1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	EYA1

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
EYA1	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	EYA1

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)
EYA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.