Usher syndrome type 1F

Summary

Usher syndrome type 1F (MONDO:0011186) is a disease caused by PCDH15 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PCDH15 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 957
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome type 1F
Mondo ID	MONDO:0011186
OMIM	602083
DOID	DOID:0110832
UMLS	C1865885
MedGen	356393
GARD	0010043
Is cancer (heuristic)	no

Also known as: USH1F · Usher syndrome type 1F · Usher syndrome, type 1F · USHER syndrome, type IF

Data availability: 957 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 1 › Usher syndrome type 1F

Related subtypes (8): Usher syndrome type 1C, Usher syndrome type 1D, Usher syndrome type 1E, Usher syndrome type 1G, Usher syndrome type 1H, Usher syndrome type 1K, Usher syndrome, type 1D/F, Usher syndrome type 1B

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

600 retrieved; paginated sample, class counts are floors:

298 uncertain significance, 67 likely pathogenic, 63 conflicting classifications of pathogenicity, 54 pathogenic/likely pathogenic, 36 pathogenic, 34 benign, 30 likely benign, 18 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4056479	Single allele	LOC105378311	Pathogenic	criteria provided, single submitter
1027565	NM_001384140.1(PCDH15):c.3667_3668del (p.Ile1223fs)	PCDH15	Pathogenic	no assertion criteria provided
1065906	NM_001384140.1(PCDH15):c.3501+2T>C	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068808	NM_033056.4(PCDH15):c.4409_4413del (p.Asn1470fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070354	NM_033056.4(PCDH15):c.4523_4526dup (p.Ala1510fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071287	NM_001384140.1(PCDH15):c.1977_1978del (p.Arg659fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073476	NM_001384140.1(PCDH15):c.3717+1G>T	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074170	NM_001384140.1(PCDH15):c.1401del (p.Gln467fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074783	NM_033056.4(PCDH15):c.4599_4600dup (p.Ser1534fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076811	NM_001384140.1(PCDH15):c.4102G>T (p.Glu1368Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076917	NM_033056.4(PCDH15):c.4699_4715dup (p.Leu1573fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339715	NM_001384140.1(PCDH15):c.3495_3496del (p.Arg1165fs)	PCDH15	Pathogenic	criteria provided, single submitter
1343721	NM_001384140.1(PCDH15):c.423_430dup (p.Ser144fs)	PCDH15	Pathogenic	criteria provided, multiple submitters, no conflicts
1362284	NM_001384140.1(PCDH15):c.3433C>T (p.Gln1145Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404217	NM_001384140.1(PCDH15):c.561dup (p.Glu188fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405236	NM_001384140.1(PCDH15):c.1831C>T (p.Gln611Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425442	NM_001384140.1(PCDH15):c.2029_2044del (p.Asp677fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451139	NM_033056.4(PCDH15):c.4566_4569dup (p.Ala1524fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451278	NM_001384140.1(PCDH15):c.3688A>T (p.Lys1230Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452598	NM_033056.4(PCDH15):c.4596_4600dup (p.Ser1534delinsThrTer)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453347	NM_001384140.1(PCDH15):c.960_967del (p.Gly321fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453439	NM_001384140.1(PCDH15):c.1529del (p.Pro510fs)	PCDH15	Pathogenic	criteria provided, multiple submitters, no conflicts
1454964	NM_001384140.1(PCDH15):c.2630T>A (p.Leu877Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455910	NM_033056.4(PCDH15):c.4411_4412dup (p.Val1472fs)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459364	NM_001384140.1(PCDH15):c.1399C>T (p.Gln467Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687300	NM_001384140.1(PCDH15):c.60_61del (p.Leu20_Phe21insTer)	PCDH15	Pathogenic	criteria provided, multiple submitters, no conflicts
1725956	NM_001384140.1(PCDH15):c.251G>A (p.Trp84Ter)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177724	NM_001384140.1(PCDH15):c.1927C>T (p.Arg643Ter)	PCDH15	Pathogenic	criteria provided, multiple submitters, no conflicts
18429	NM_001384140.1(PCDH15):c.1583T>A (p.Val528Asp)	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189083	NM_001384140.1(PCDH15):c.3717+1G>A	PCDH15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
PCDH15	Definitive	Unknown	Usher syndrome type 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCDH15	Orphanet:231169	Usher syndrome type 1
PCDH15	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ZFHX4	Orphanet:91411	Congenital ptosis

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
PCDH15	HGNC:14674	ENSG00000150275	Q96QU1	Protocadherin-15	gencc,clinvar
ZFHX4	HGNC:30939	ENSG00000091656	Q86UP3	Zinc finger homeobox protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCDH15	Protocadherin-15	Calcium-dependent cell-adhesion protein.
ZFHX4	Zinc finger homeobox protein 4	May play a role in neural and muscle differentiation.

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)
PCDH15	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ZFHX4	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, 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
adrenal tissue	2
left adrenal gland cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCDH15	130	tissue_specific	marker	left adrenal gland cortex, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
ZFHX4	230	ubiquitous	marker	calcaneal tendon, tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCDH15	1,732
ZFHX4	1,255

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCDH15	Q96QU1	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZFHX4	Q86UP3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Sensory processing of sound by outer hair cells of the cochlea	1	203.9×	0.006	PCDH15
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.006	PCDH15

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
equilibrioception	1	1203.7×	0.004	PCDH15
sensory perception of light stimulus	1	936.2×	0.004	PCDH15
inner ear development	1	187.2×	0.011	PCDH15
photoreceptor cell maintenance	1	179.3×	0.011	PCDH15
homophilic cell-cell adhesion	1	70.2×	0.023	PCDH15
sensory perception of sound	1	50.5×	0.026	PCDH15
cell adhesion	1	18.7×	0.060	PCDH15
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZFHX4

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
PCDH15	0	0
ZFHX4	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
PCDH15	9	Binding:9

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	PCDH15, ZFHX4

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)
PCDH15	9	—
ZFHX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns