Usher Syndrome Type 2

Mendelian MONDO:0016484 Pathograph 16 Show in embeddings browser Inherited retinal dystrophy Sensorineural hearing loss

Usher syndrome type 2 is the mechanism entity in which biallelic loss of a component of the ankle-link complex - usherin (USH2A), ADGRV1/VLGR1, and whirlin (WHRN), with PDZD7 as a modifier - produces sloping congenital sensorineural hearing loss, generally intact vestibular function, and later-onset retinitis pigmentosa. Two things separate this from Usher syndrome type 1, and both are structural rather than a matter of severity. First, the ankle-link complex is a TRANSIENT assembly of the DEVELOPING hair bundle - whirlin and PDZD7 orchestrate ADGRV1 and usherin into a condensate by liquid-liquid phase separation, and ankle links are not present in mature stereocilia. The type-1 upper tip-link density is by contrast a tension-bearing complex of the mature bundle. The two are different assemblies acting in different developmental windows, which is why the auditory phenotype here is a sloping loss rather than the profound congenital loss of type 1, and why vestibular function is usually spared. Second, in the retina the type-2 proteins sit at the periciliary membrane compartment, a photoreceptor ciliary trafficking site. That is a different subcellular compartment from the calyceal-process adhesion belt that carries the type-1 retinal mechanism. Harmonin (USH1C) is annotated to both complexes. That is not an artifact: harmonin PDZ1 binds the C-terminal PDZ-binding motifs of both usherin and ADGRV1, so it is a deliberate physical bridge between the type-1 and type-2 networks. It is curated as a type-1 gene because the tension-bearing tip-link role is the one whose loss gives the type-1 presentation.

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2
Inheritance
5
Pathophys.
7
Phenotypes
16
Pathograph
4
Genes
5
Medical Actions
3
Subtypes
1
Trials
1
Models
15
References
👪

Inheritance

2
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child"
Confirms the autosomal recessive inheritance and recurrence risk of type 2.
Digenic inheritance HP:0010984
A subset of type-2 disease shows digenic inheritance, in which a heterozygous PDZD7 variant contributes together with a variant in a second type-2 gene. PDZD7 also acts as a retinal disease modifier. This is curated on the type-2 entity specifically because PDZD7 is a member of the ankle-link complex, and the reported digenic partners are ADGRV1 and USH2A.
Digenic inheritance
Show evidence (1 reference)
PMID:20440071 SUPPORT Human Clinical
"Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus."
A heterozygous truncating PDZD7 variant was found in patients who also carried mutations in a second type-2 gene, supporting a digenic contribution.
◆

Subtypes

3
Usher syndrome type 2A (USH2A, usherin) MONDO:0010169
USH2A hgnc:12601 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in USH2A (hgnc:12601). hgnc:12601 is a gene from the HUGO Gene Nomenclature Committee.
The predominant type-2 locus, accounting for approximately 80% of type-2 cases. Usherin is the transmembrane core of the ankle-link complex.
Show evidence (2 references)
PMID:32995707 SUPPORT Human Clinical
"To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome."
Quantifies USH2A as the predominant type-2 locus.
PMID:9624053 SUPPORT Human Clinical
"Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region."
Primary report assigning the USH2A locus to the USH2A gene, which is the gene-to-locus assignment this row binds to MONDO:0010169.
Usher syndrome type 2C (ADGRV1) MONDO:0011558
ADGRV1 hgnc:17416 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ADGRV1 (hgnc:17416). hgnc:17416 is a gene from the HUGO Gene Nomenclature Committee.
ADGRV1 (formerly GPR98/VLGR1) is the very large adhesion GPCR of the ankle-link complex.
Show evidence (3 references)
CGGV:assertion_992d2cd7-5305-4278-9601-3e59ac1a8770-2017-02-15T170000.000Z SUPPORT Other
"ADGRV1 | HGNC:17416 | Usher syndrome type 2 | MONDO:0016484 | AR | Definitive | SOP4 | Hearing Loss Gene Curation Expert Panel"
ClinGen classifies the ADGRV1-type 2 relationship as Definitive against this entry's own MONDO term.
PMID:20301515 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
GeneReviews states the biallelic requirement for ADGRV1, which is what this row asserts and what the MONDO definition of MONDO:0011558 does not.
PMID:14740321 SUPPORT Human Clinical
"identified four isoform-specific VLGR1 mutations (Q2301X, I2906FS, M2931FS, and T6244X) from three families with USH2C, as well as two sporadic cases"
Primary report assigning the USH2C locus to the gene now approved as ADGRV1, under its then-current symbol VLGR1. This is the gene-to-locus assignment this row binds to MONDO:0011558, the term for which MONDO itself records no causal gene.
Usher syndrome type 2D (WHRN, whirlin) MONDO:0012662
WHRN hgnc:16361 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in WHRN (hgnc:16361). hgnc:16361 is a gene from the HUGO Gene Nomenclature Committee.
Whirlin heterodimerizes with PDZD7 and, together with it, is required for assembly of the quaternary ankle-link complex with usherin and ADGRV1. Held as a subtype rather than promoted to its own entry, although ClinGen curates WHRN against a distinct MONDO term (Usher syndrome type 2D, MONDO:0012662) rather than against the type-2 term this entry binds. The mechanism is the same ankle-link assembly, so the disjunction test that justified separating the four Usher entities is not met here: there is no pathophysiology node that is true of USH2D and untrue of USH2A or USH2C. Recorded explicitly rather than flattened, because the external curation does draw a boundary here and a later reviewer should see that it was considered.
Show evidence (2 references)
PMID:20301515 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
Confirms WHRN as one of the three established type-2 genes.
PMID:17171570 SUPPORT Human Clinical
"We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin."
Primary report naming USH2D and assigning it to whirlin, approved symbol WHRN, which is the gene-to-locus assignment this row binds to MONDO:0012662.
⚙

Pathophysiology

5
Hair Cell Mechanotransduction Failure
Impaired cochlear hair cell transduction, most marked at high frequencies. Unlike type 1, vestibular hair cell function is generally intact or only variably affected.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Sloping Congenital Sensorineural Hearing Loss Partial transduction failure produces congenital hearing loss that is mild to moderate in the low frequencies and severe to profound in the high frequencies.
Show evidence (1 reference)
PMID:33193648 SUPPORT REVIEW SYNTHESIS Other
"Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction."
Links Usher-gene bundle-morphology defects to inhibited mechanosensory transduction.
Photoreceptor Periciliary Membrane Complex Disruption
Usherin, ADGRV1 and whirlin localize to the photoreceptor periciliary membrane compartment, a ciliary trafficking site at the base of the connecting cilium, where the interactome is implicated in protein trafficking between the inner and outer segments. This is the compartment the lumped entry's single "Photoreceptor Connecting Cilium Dysfunction" node described. It is correct for this entity and was not correct for types 1 and 3, which is one of the reasons the split was made.
retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology. photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
protein localization to cilium GO:0061512 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein localization to cilium (GO:0061512). GO:0061512 is a biological process from the Gene Ontology. ⚠ ABNORMAL
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pdzd7 interaction zebrafish model Zebrafish (Danio rerio) partially recapitulates Combined perturbation changes retinal cell survival and Gpr98 localization near the photoreceptor connecting cilium.
Downstream
Photoreceptor Degeneration Impaired intersegmental trafficking and outer-segment maintenance are followed by progressive photoreceptor loss.
Show evidence (1 reference)
PMID:24239741 SUPPORT REVIEW SYNTHESIS Model Organism
"Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate..."
Locates the Usher interactome at the periciliary region and implicates it in intersegmental trafficking.
Photoreceptor Degeneration
Progressive rod-then-cone degeneration, with a later onset than in type 1.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
visual perception GO:0007601 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased visual perception (GO:0007601). GO:0007601 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Retinitis Pigmentosa Progressive photoreceptor loss manifests clinically as retinitis pigmentosa.
Night Blindness Early rod loss produces nyctalopia.
Constricted Visual Fields Peripheral rod loss constricts the visual field.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
Establishes the rod-then-cone clinical progression in type 2.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Usher Syndrome Type 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Ear 1
Sloping Congenital Sensorineural Hearing Loss Congenital sensorineural hearing impairment HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital sensorineural hearing impairment (HP:0008527). HP:0008527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Intact or variable vestibular responses."
Establishes the sloping congenital hearing loss of type 2.
Eye 6
Retinitis Pigmentosa Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510), qualified as course progressive. HP:0000510 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:32995707 SUPPORT Human Clinical
"Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction."
Establishes retinitis pigmentosa as a defining feature.
Night Blindness Nyctalopia HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
Documents night blindness as the first retinal symptom.
Constricted Visual Fields Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constriction of peripheral visual field (HP:0001133), qualified as course progressive. HP:0001133 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision)"
Documents progressive visual-field constriction.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"detect potentially treatable complications such as cataracts, refractive errors, and cystoid macular edema."
Lists cataract among treatable complications detected on surveillance in type 2.
Cystoid Macular Edema HP:0011505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystoid macular edema (HP:0011505). HP:0011505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"detect potentially treatable complications such as cataracts, refractive errors, and cystoid macular edema."
Names cystoid macular edema among the treatable complications surveillance detects in type 2.
Abnormal Electroretinogram HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function."
Supports retinal electrophysiology as part of the diagnostic evaluation.
🧬

Genetic Associations

4
USH2A (Causative)
Gene: USH2A hgnc:12601 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is USH2A (hgnc:12601). hgnc:12601 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:32995707 SUPPORT Human Clinical
"To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome."
Quantifies USH2A as the predominant type-2 locus.
PMID:33895329 SUPPORT Human Clinical
"Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13."
Establishes exon 13 as the site of the two most common USH2A pathogenic variants.
ADGRV1 (Causative)
Gene: ADGRV1 hgnc:17416 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADGRV1 (hgnc:17416). hgnc:17416 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
CGGV:assertion_992d2cd7-5305-4278-9601-3e59ac1a8770-2017-02-15T170000.000Z SUPPORT Other
"ADGRV1 | HGNC:17416 | Usher syndrome type 2 | MONDO:0016484 | AR | Definitive | SOP4 | Hearing Loss Gene Curation Expert Panel"
ClinGen classifies the ADGRV1-type 2 relationship as Definitive.
WHRN (Causative)
Gene: WHRN hgnc:16361 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WHRN (hgnc:16361). hgnc:16361 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25406310 SUPPORT In Vitro
"Interaction between WHRN and PDZD7 is the bridge between USH2A and GPR98."
Establishes whirlin's structural role in the complex that defines this entity.
PMID:20301515 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
Confirms WHRN as an established type-2 gene.
PDZD7 (Modifier)
Gene: PDZD7 hgnc:26257 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDZD7 (hgnc:26257). hgnc:26257 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:20440071 SUPPORT Model Organism
"We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A."
Supports both the digenic contribution and the retinal-modifier role of PDZD7.
💊

Medical Actions

5
Hearing Aids
Platform: Device
Early hearing-aid fitting with speech training. Amplification rather than implantation is the usual first step here, because the type-2 loss is sloping and leaves useful low-frequency hearing.
Target Phenotypes: Congenital sensorineural hearing impairment HP:0008527 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congenital sensorineural hearing impairment (HP:0008527). HP:0008527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Treatment of manifestations: Early fitting of hearing aids and speech training."
GeneReviews recommends early hearing-aid fitting and speech training for type 2.
Low-Vision Rehabilitation and Psychosocial Support
Platform: Behavioral / lifestyle
Orientation and adaptive-skills training as vision declines, with vocational rehabilitation and mental-health support.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
Establishes the progressive vision loss that low-vision rehabilitation addresses. The cited GeneReviews abstract does not itself state a low-vision rehabilitation recommendation for type 2, so this treatment is recorded on the disease course rather than on a quoted recommendation.
Audiologic and Ophthalmologic Surveillance
Annual multimodal retinal surveillance from age ten years, with audiologic follow-up for device users.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Annual fundus photography, visual acuity, visual field, electroretinography, optical coherence tomography, and fundus autofluorescence from age ten years."
Supports annual retinal surveillance from age ten in type 2.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses the autosomal recessive recurrence risk, and in this entity also the possibility of a digenic PDZD7 contribution.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child"
Supports counseling for the autosomal recessive recurrence risk.
Ultevursen (QR-421a)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide Splice modulation (exon skipping) Delivery: Unformulated (free uptake) Targeting: Unconjugated
RNA target: USH2A hgnc:12601 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of USH2A (hgnc:12601). hgnc:12601 is a gene from the HUGO Gene Nomenclature Committee. USH2A pre-mRNA exon 13
Investigational antisense oligonucleotide inducing skipping of USH2A exon 13, which carries the two recurrent pathogenic variants c.2299delG and c.2276G>T. Exon skipping is intended to produce a shortened usherin protein. Evaluated by intravitreal injection in the Phase 2b LUNA trial.
Mechanism Target:
MODULATES Ankle-Link Complex Assembly Failure — In the USH2A exon-13 molecular subgroup, QR-421a induces exon 13 skipping upstream of the complex-assembly defect. This does not assert restored human complex function or clinical efficacy.
Show evidence (1 reference)
PMID:33895329 SUPPORT In Vitro
"Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation."
Supports splice modulation in patient-derived photoreceptor precursors, scoped to USH2A exon 13.
Show evidence (2 references)
PMID:33895329 SUPPORT In Vitro
"Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation."
Patient-derived photoreceptor-precursor evidence supports QR-421a-mediated exon 13 skipping; it does not establish clinical efficacy.
clinicaltrials:NCT06627179 SUPPORT Human Clinical
"The purpose of this Phase 2b study is to evaluate the safety and tolerability of ultevursen administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene."
Registry record confirming Phase 2b evaluation, route, and molecular scope.
🔬

Diagnosis

2
Audiologic and retinal functional evaluation
Establish the clinical phenotype with subjective and electrophysiologic hearing and retinal testing. A sloping congenital loss with intact vestibular responses is the type-2 pattern.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function."
Establishes the clinical diagnostic route for type 2.
Molecular genetic confirmation
Identify biallelic pathogenic variants in one of the three type-2 genes.
Show evidence (1 reference)
PMID:20301515 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
Establishes molecular confirmation for the three type-2 genes.
🔬

Clinical Trials

1
NCT06627179 PHASE_II ACTIVE_NOT_RECRUITING
Double-masked, randomized, sham-controlled Phase 2b LUNA study of intravitreal ultevursen in 81 participants with retinitis pigmentosa due to USH2A exon 13 mutations. Registry status as recorded in the cached record retrieved 2026-08-11; not re-checked for this split.
Target Phenotypes: Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06627179 SUPPORT Human Clinical
"This is a multicenter Double-masked, Randomized, Sham-controlled study which will enroll 81 subjects."
Establishes the LUNA design and planned enrollment.
🐁

Animal Models

1
Pdzd7 interaction zebrafish model Knockdown interaction model
Pdzd7 knockdown produces an Usher-like phenotype and worsens retinal cell death when combined with ush2a or gpr98 perturbation. It supports genetic interaction and retinal-modifier biology within the type-2 complex and does not reproduce the full human auditory-retinal disease.
Retinal cell death
Species
Zebrafish (Danio rerio)
Genotype
Pdzd7 knockdown alone and in combination with ush2a or gpr98 perturbation
Pathograph links
Photoreceptor Periciliary Membrane Complex Disruption partially recapitulates fidelity: low observes: cellular Combined perturbation changes retinal cell survival and Gpr98 localization near the photoreceptor connecting cilium.
Limitations: Knockdown in zebrafish is a developmental perturbation and does not establish the magnitude or clinical course of PDZD7 modification in humans.
Show evidence (1 reference)
PMID:20440071 SUPPORT Model Organism
"Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium."
Supports the model's genetic-interaction and connecting-cilium readouts.
Show evidence (1 reference)
PMID:20440071 SUPPORT Model Organism
"We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A."
Supports use of the zebrafish experiment to test digenic and modifier hypotheses.
{ }

Source YAML

click to show 
name: Usher Syndrome Type 2
creation_date: "2026-09-24T00:00:00Z"
category: Mendelian
synonyms:
- USH2
- Usher syndrome type II
- Usher syndrome type 2
description: >
  Usher syndrome type 2 is the mechanism entity in which biallelic loss of a
  component of the ankle-link complex - usherin (USH2A), ADGRV1/VLGR1, and
  whirlin (WHRN), with PDZD7 as a modifier - produces sloping congenital
  sensorineural hearing loss, generally intact vestibular function, and
  later-onset retinitis pigmentosa.

  Two things separate this from Usher syndrome type 1, and both are structural
  rather than a matter of severity. First, the ankle-link complex is a TRANSIENT
  assembly of the DEVELOPING hair bundle - whirlin and PDZD7 orchestrate ADGRV1
  and usherin into a condensate by liquid-liquid phase separation, and ankle
  links are not present in mature stereocilia. The type-1 upper tip-link density
  is by contrast a tension-bearing complex of the mature bundle. The two are
  different assemblies acting in different developmental windows, which is why
  the auditory phenotype here is a sloping loss rather than the profound
  congenital loss of type 1, and why vestibular function is usually spared.

  Second, in the retina the type-2 proteins sit at the periciliary membrane
  compartment, a photoreceptor ciliary trafficking site. That is a different
  subcellular compartment from the calyceal-process adhesion belt that carries
  the type-1 retinal mechanism.

  Harmonin (USH1C) is annotated to both complexes. That is not an artifact:
  harmonin PDZ1 binds the C-terminal PDZ-binding motifs of both usherin and
  ADGRV1, so it is a deliberate physical bridge between the type-1 and type-2
  networks. It is curated as a type-1 gene because the tension-bearing tip-link
  role is the one whose loss gives the type-1 presentation.
disease_term:
  preferred_term: Usher syndrome type 2
  term:
    id: MONDO:0016484
    label: Usher syndrome type 2
parents:
- Inherited retinal dystrophy
- Sensorineural hearing loss
references:
- reference: PMID:20301515
  title: "Usher Syndrome Type II."
  tags:
  - GeneReviews
- reference: PMID:24239741
  title: Usher protein functions in hair cells and photoreceptors.
- reference: PMID:25406310
  title: Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.
- reference: PMID:32995707
  title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
- reference: PMID:33193648
  title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
- reference: PMID:33895329
  title: Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.
- reference: PMID:35353227
  title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
- reference: PMID:36964137
  title: Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.
- reference: PMID:20440071
  title: PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome.
- reference: CGGV:assertion_992d2cd7-5305-4278-9601-3e59ac1a8770-2017-02-15T170000.000Z
  title: "ADGRV1 / Usher syndrome type 2 (Definitive)"
- reference: clinicaltrials:NCT06627179
  title: A Two-Year Double-masked, Randomized, Sham-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
- reference: PMID:30531642
  title: "Genetics of Usher Syndrome: New Insights From a Meta-analysis."
- reference: PMID:9624053
  title: Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.
- reference: PMID:14740321
  title: Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II.
- reference: PMID:17171570
  title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child"
    explanation: Confirms the autosomal recessive inheritance and recurrence risk of type 2.
- name: Digenic inheritance
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    A subset of type-2 disease shows digenic inheritance, in which a heterozygous
    PDZD7 variant contributes together with a variant in a second type-2 gene.
    PDZD7 also acts as a retinal disease modifier. This is curated on the type-2
    entity specifically because PDZD7 is a member of the ankle-link complex, and
    the reported digenic partners are ADGRV1 and USH2A.
  evidence:
  - reference: PMID:20440071
    reference_title: "PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, heterozygous PDZD7 mutations were present in patients with
      truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also
      known as USH2C), and an unidentified locus.
    explanation: >-
      A heterozygous truncating PDZD7 variant was found in patients who also
      carried mutations in a second type-2 gene, supporting a digenic contribution.
has_subtypes:
- name: USH2A
  display_name: Usher syndrome type 2A (USH2A, usherin)
  subtype_term:
    preferred_term: Usher syndrome type 2A
    term:
      id: MONDO:0010169
      label: Usher syndrome type 2A
  description: >-
    The predominant type-2 locus, accounting for approximately 80% of type-2
    cases. Usherin is the transmembrane core of the ankle-link complex.
  genes:
  - preferred_term: USH2A
    term:
      id: hgnc:12601
      label: USH2A
  evidence:
  - reference: PMID:32995707
    reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome."
    explanation: Quantifies USH2A as the predominant type-2 locus.
  - reference: PMID:9624053
    reference_title: Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region."
    explanation: >-
      Primary report assigning the USH2A locus to the USH2A gene, which is the gene-to-locus
      assignment this row binds to MONDO:0010169.
- name: USH2C
  display_name: Usher syndrome type 2C (ADGRV1)
  subtype_term:
    preferred_term: Usher syndrome type 2C
    term:
      id: MONDO:0011558
      label: Usher syndrome type 2C
  description: >-
    ADGRV1 (formerly GPR98/VLGR1) is the very large adhesion GPCR of the
    ankle-link complex.
  genes:
  - preferred_term: ADGRV1
    term:
      id: hgnc:17416
      label: ADGRV1
  evidence:
  - reference: CGGV:assertion_992d2cd7-5305-4278-9601-3e59ac1a8770-2017-02-15T170000.000Z
    reference_title: "ADGRV1 / Usher syndrome type 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ADGRV1 | HGNC:17416 | Usher syndrome type 2 | MONDO:0016484 | AR | Definitive | SOP4 | Hearing Loss Gene Curation Expert Panel"
    explanation: ClinGen classifies the ADGRV1-type 2 relationship as Definitive against this entry's own MONDO term.
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
    explanation: >-
      GeneReviews states the biallelic requirement for ADGRV1, which is what this row
      asserts and what the MONDO definition of MONDO:0011558 does not.
  - reference: PMID:14740321
    reference_title: Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified four isoform-specific VLGR1 mutations (Q2301X, I2906FS, M2931FS, and T6244X) from three families with USH2C, as well as two sporadic cases"
    explanation: >-
      Primary report assigning the USH2C locus to the gene now approved as ADGRV1, under its
      then-current symbol VLGR1. This is the gene-to-locus assignment this row binds to
      MONDO:0011558, the term for which MONDO itself records no causal gene.
- name: USH2D
  display_name: Usher syndrome type 2D (WHRN, whirlin)
  subtype_term:
    preferred_term: Usher syndrome type 2D
    term:
      id: MONDO:0012662
      label: Usher syndrome type 2D
  description: >-
    Whirlin heterodimerizes with PDZD7 and, together with it, is required for
    assembly of the quaternary ankle-link complex with usherin and ADGRV1.

    Held as a subtype rather than promoted to its own entry, although ClinGen
    curates WHRN against a distinct MONDO term (Usher syndrome type 2D,
    MONDO:0012662) rather than against the type-2 term this entry binds. The
    mechanism is the same ankle-link assembly, so the disjunction test that
    justified separating the four Usher entities is not met here: there is no
    pathophysiology node that is true of USH2D and untrue of USH2A or USH2C.
    Recorded explicitly rather than flattened, because the external curation does
    draw a boundary here and a later reviewer should see that it was considered.
  genes:
  - preferred_term: WHRN
    term:
      id: hgnc:16361
      label: WHRN
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
    explanation: Confirms WHRN as one of the three established type-2 genes.
  - reference: PMID:17171570
    reference_title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin."
    explanation: >-
      Primary report naming USH2D and assigning it to whirlin, approved symbol WHRN, which is
      the gene-to-locus assignment this row binds to MONDO:0012662.
pathophysiology:
- name: Ankle-Link Complex Assembly Failure
  genes:
  - preferred_term: USH2A
    term:
      id: hgnc:12601
      label: USH2A
  - preferred_term: ADGRV1
    term:
      id: hgnc:17416
      label: ADGRV1
  - preferred_term: WHRN
    term:
      id: hgnc:16361
      label: WHRN
  - preferred_term: PDZD7
    term:
      id: hgnc:26257
      label: PDZD7
  subtypes:
  - USH2A
  - USH2C
  - USH2D
  description: >-
    Biallelic loss of usherin, ADGRV1 or whirlin prevents assembly of the
    ankle-link complex at the ankle region of developing stereocilia. Whirlin and
    PDZD7 heterodimerize and orchestrate usherin and ADGRV1 into the complex
    through liquid-liquid phase separation; both scaffolds are required, and the
    whirlin-PDZD7 interaction is the bridge between usherin and ADGRV1.

    This is a transient developmental assembly, not the mature tension-bearing
    complex that carries the type-1 mechanism.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  downstream:
  - target: Developing Hair Bundle Ankle-Link Loss
    description: >-
      Without the quaternary complex, ankle links do not form at the ankle region
      of developing stereocilia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36964137
      reference_title: Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Disruption of the ALC multivalency for LLPS largely abolishes the distribution of WHRN at the ankle region of stereocilia."
      explanation: Shows that disrupting complex assembly removes the scaffold from the ankle region.
  - target: Photoreceptor Periciliary Membrane Complex Disruption
    description: >-
      The same proteins form the periciliary membrane complex in photoreceptors,
      so the retinal branch is a parallel consequence of the same lesion rather
      than a sequel to the cochlear one.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24239741
      reference_title: "Usher protein functions in hair cells and photoreceptors."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors."
      explanation: Locates an Usher protein interactome at the photoreceptor periciliary region.
  evidence:
  - reference: PMID:36964137
    reference_title: Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS)."
    explanation: Establishes the composition and assembly mechanism of the ankle-link complex that defines this entity.
  - reference: PMID:25406310
    reference_title: Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98."
    explanation: Establishes that both scaffolds are required for the quaternary complex.
- name: Developing Hair Bundle Ankle-Link Loss
  description: >-
    Ankle links interconnect the ankle region of developing stereocilia and are
    essential for stereocilia development. Their absence disturbs bundle
    development, but because the complex is transient and is not the mature
    tension-bearing element, the resulting transduction deficit is partial rather
    than complete - the clinical correlate being a sloping loss that is worse at
    high frequencies, with vestibular function usually preserved.
  biological_scale: TISSUE
  locations:
  - preferred_term: spiral organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  biological_processes:
  - preferred_term: mechanoreceptor differentiation
    term:
      id: GO:0042490
      label: mechanoreceptor differentiation
    modifier: ABNORMAL
  downstream:
  - target: Hair Cell Mechanotransduction Failure
    description: >-
      Disturbed bundle development impairs mechanotransduction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33193648
      reference_title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction."
      explanation: >-
        Links stereocilia bundle morphology defects to inhibited mechanosensory
        transduction. Quoted for the bundle-morphology clause; the tip-link clause
        in the same sentence describes the type-1 mechanism, not this one.
  evidence:
  - reference: PMID:36964137
    reference_title: Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ankle links connect the ankle region of developing stereocilia, playing an essential role in stereocilia development."
    explanation: States the developmental role and transient location of the structure lost in this entity.
- name: Hair Cell Mechanotransduction Failure
  description: >-
    Impaired cochlear hair cell transduction, most marked at high frequencies.
    Unlike type 1, vestibular hair cell function is generally intact or only
    variably affected.
  biological_scale: CELLULAR
  conforms_to: "sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death"
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  downstream:
  - target: Sloping Congenital Sensorineural Hearing Loss
    description: >-
      Partial transduction failure produces congenital hearing loss that is mild
      to moderate in the low frequencies and severe to profound in the high
      frequencies.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301515
      reference_title: "Usher Syndrome Type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Intact or variable vestibular responses."
      explanation: Establishes the sloping congenital hearing loss and preserved vestibular responses of type 2.
  evidence:
  - reference: PMID:33193648
    reference_title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction."
    explanation: Links Usher-gene bundle-morphology defects to inhibited mechanosensory transduction.
- name: Photoreceptor Periciliary Membrane Complex Disruption
  description: >-
    Usherin, ADGRV1 and whirlin localize to the photoreceptor periciliary
    membrane compartment, a ciliary trafficking site at the base of the
    connecting cilium, where the interactome is implicated in protein trafficking
    between the inner and outer segments.

    This is the compartment the lumped entry's single "Photoreceptor Connecting
    Cilium Dysfunction" node described. It is correct for this entity and was not
    correct for types 1 and 3, which is one of the reasons the split was made.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  biological_processes:
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: ABNORMAL
  downstream:
  - target: Photoreceptor Degeneration
    description: >-
      Impaired intersegmental trafficking and outer-segment maintenance are
      followed by progressive photoreceptor loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired intraciliary protein transport
    - outer-segment homeostatic failure
    evidence:
    - reference: PMID:24239741
      reference_title: "Usher protein functions in hair cells and photoreceptors."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors."
      explanation: >-
        Supports a provisional trafficking model. The cited sentence says
        "suggests", and the primary result it summarizes is from a type-1 mouse
        model, so this is recorded as a provisional mechanism rather than an
        established one for this entity.
  evidence:
  - reference: PMID:24239741
    reference_title: "Usher protein functions in hair cells and photoreceptors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors."
    explanation: Locates the Usher interactome at the periciliary region and implicates it in intersegmental trafficking.
- name: Photoreceptor Degeneration
  description: >-
    Progressive rod-then-cone degeneration, with a later onset than in type 1.
  biological_scale: TISSUE
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: visual perception
    term:
      id: GO:0007601
      label: visual perception
    modifier: DECREASED
  downstream:
  - target: Retinitis Pigmentosa
    description: Progressive photoreceptor loss manifests clinically as retinitis pigmentosa.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301515
      reference_title: "Usher Syndrome Type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
      explanation: Defines the progressive retinal degeneration of type 2.
  - target: Night Blindness
    description: Early rod loss produces nyctalopia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301515
      reference_title: "Usher Syndrome Type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
      explanation: Links the retinal degeneration to night blindness as its first symptom.
  - target: Constricted Visual Fields
    description: Peripheral rod loss constricts the visual field.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301515
      reference_title: "Usher Syndrome Type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision)"
      explanation: Documents progressive visual-field constriction.
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
    explanation: Establishes the rod-then-cone clinical progression in type 2.
phenotypes:
- category: Auditory
  name: Sloping Congenital Sensorineural Hearing Loss
  description: >-
    Congenital bilateral sensorineural hearing loss, mild to moderate in the low
    frequencies and severe to profound in the high frequencies. The sloping
    configuration is what distinguishes the type-2 audiogram from the uniformly
    profound loss of type 1.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Intact or variable vestibular responses."
    explanation: Establishes the sloping congenital hearing loss of type 2.
- category: Ophthalmologic
  name: Retinitis Pigmentosa
  description: >-
    Progressive rod-cone dystrophy, later in onset than in type 1.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32995707
    reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction."
    explanation: Establishes retinitis pigmentosa as a defining feature.
- category: Ophthalmologic
  name: Night Blindness
  description: >-
    Nyctalopia is the presenting retinal symptom.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
    explanation: Documents night blindness as the first retinal symptom.
- category: Ophthalmologic
  name: Constricted Visual Fields
  description: >-
    Progressive peripheral field constriction ("tunnel vision").
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision)"
    explanation: Documents progressive visual-field constriction.
- category: Ophthalmologic
  name: Cataract
  description: >-
    Cataract is a potentially treatable ophthalmologic complication monitored
    during surveillance.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "detect potentially treatable complications such as cataracts, refractive errors, \nand cystoid macular edema."
    explanation: Lists cataract among treatable complications detected on surveillance in type 2.
- category: Ophthalmologic
  name: Cystoid Macular Edema
  description: >-
    Cystoid macular edema is a potentially treatable complication that
    surveillance is intended to detect. It matters clinically out of proportion to
    its mechanism here: unlike the photoreceptor degeneration it accompanies, it
    is often responsive to treatment, so detecting it is one of the few points
    where retinal surveillance changes management.
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "detect potentially treatable complications such as cataracts, refractive errors, \nand cystoid macular edema."
    explanation: >-
      Names cystoid macular edema among the treatable complications surveillance
      detects in type 2.
- category: Ophthalmologic
  name: Abnormal Electroretinogram
  description: >-
    Electroretinography is part of the diagnostic evaluation and of annual
    retinal surveillance.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  reports_on:
  - target: Photoreceptor Degeneration
    relationship: READOUT_OF
    endpoint_context: DIAGNOSTIC
    interpretation: Decreased electroretinographic responses report photoreceptor dysfunction.
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function."
    explanation: Supports retinal electrophysiology as part of the diagnostic evaluation.
genetic:
- name: USH2A
  association: Causative
  subtype: USH2A
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: USH2A
    term:
      id: hgnc:12601
      label: USH2A
  features: >-
    Usherin, the transmembrane core of the ankle-link complex and the predominant
    type-2 locus. The two most recurrent pathogenic variants both lie in exon 13,
    which is the basis for the exon-skipping therapeutic strategy.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 50.0
    cohort_size: 684
    notes: >-
      341 of 684 patients carried biallelic variants in this gene. The denominator is
      all Usher syndrome rather than this entry's clinical type, because that is the
      cohort the meta-analysis reports.
    evidence:
    - reference: PMID:30531642
      reference_title: "Genetics of Usher Syndrome: New Insights From a Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the biallelic disease-causing mutation rate was assessed for each Usher gene to propose a classification by frequency: USH2A: 50% (341/684) of patients, MYO7A: 21% (144/684), CDH23: 6% (39/684), ADGRV1: 5% (35/684), PCDH15: 3% (21/684), USH1C: 2% (17/684), CLRN1: 2% (14/684), USH1G: 1% (9/684), WHRN: 0.4% (3/684), PDZD7 0.1% (1/684), CIB2 (0/684)"
      explanation: Meta-analysis biallelic mutation rate for this gene across all Usher syndrome patients.
  - population: Usher syndrome type 2 (literature review)
    case_fraction_percent: 80.0
    notes: The review gives approximately 80% of type 2.
    evidence:
    - reference: PMID:32995707
      reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome."
      explanation: Type-specific share of type-2 cases attributable to USH2A.
  evidence:
  - reference: PMID:32995707
    reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome."
    explanation: Quantifies USH2A as the predominant type-2 locus.
  - reference: PMID:33895329
    reference_title: Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in USH2A are among the most common causes of syndromic and
      non-syndromic retinitis pigmentosa (RP). The two most recurrent
      mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13.
    explanation: Establishes exon 13 as the site of the two most common USH2A pathogenic variants.
- name: ADGRV1
  association: Causative
  subtype: USH2C
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ADGRV1
    term:
      id: hgnc:17416
      label: ADGRV1
  features: >-
    The very large adhesion GPCR of the ankle-link complex, bound by PDZD7.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 5.0
    cohort_size: 684
    notes: >-
      35 of 684 patients carried biallelic variants in this gene. The denominator is
      all Usher syndrome rather than this entry's clinical type, because that is the
      cohort the meta-analysis reports.
    evidence:
    - reference: PMID:30531642
      reference_title: "Genetics of Usher Syndrome: New Insights From a Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the biallelic disease-causing mutation rate was assessed for each Usher gene to propose a classification by frequency: USH2A: 50% (341/684) of patients, MYO7A: 21% (144/684), CDH23: 6% (39/684), ADGRV1: 5% (35/684), PCDH15: 3% (21/684), USH1C: 2% (17/684), CLRN1: 2% (14/684), USH1G: 1% (9/684), WHRN: 0.4% (3/684), PDZD7 0.1% (1/684), CIB2 (0/684)"
      explanation: Meta-analysis biallelic mutation rate for this gene across all Usher syndrome patients.
  evidence:
  - reference: CGGV:assertion_992d2cd7-5305-4278-9601-3e59ac1a8770-2017-02-15T170000.000Z
    reference_title: "ADGRV1 / Usher syndrome type 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ADGRV1 | HGNC:17416 | Usher syndrome type 2 | MONDO:0016484 | AR | Definitive | SOP4 | Hearing Loss Gene Curation Expert Panel"
    explanation: ClinGen classifies the ADGRV1-type 2 relationship as Definitive.
- name: WHRN
  association: Causative
  subtype: USH2D
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: WHRN
    term:
      id: hgnc:16361
      label: WHRN
  features: >-
    Whirlin, which heterodimerizes with PDZD7; the whirlin-PDZD7 interaction
    bridges usherin and ADGRV1 in the quaternary complex.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 0.4
    cohort_size: 684
    notes: >-
      3 of 684 patients carried biallelic variants in this gene. The denominator is
      all Usher syndrome rather than this entry's clinical type, because that is the
      cohort the meta-analysis reports.
    evidence:
    - reference: PMID:30531642
      reference_title: "Genetics of Usher Syndrome: New Insights From a Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the biallelic disease-causing mutation rate was assessed for each Usher gene to propose a classification by frequency: USH2A: 50% (341/684) of patients, MYO7A: 21% (144/684), CDH23: 6% (39/684), ADGRV1: 5% (35/684), PCDH15: 3% (21/684), USH1C: 2% (17/684), CLRN1: 2% (14/684), USH1G: 1% (9/684), WHRN: 0.4% (3/684), PDZD7 0.1% (1/684), CIB2 (0/684)"
      explanation: Meta-analysis biallelic mutation rate for this gene across all Usher syndrome patients.
  evidence:
  - reference: PMID:25406310
    reference_title: Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interaction between WHRN and PDZD7 is the bridge between USH2A and GPR98."
    explanation: Establishes whirlin's structural role in the complex that defines this entity.
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
    explanation: Confirms WHRN as an established type-2 gene.
- name: PDZD7
  association: Modifier
  relationship_type: MODIFIER
  gene_term:
    preferred_term: PDZD7
    term:
      id: hgnc:26257
      label: PDZD7
  features: >-
    PDZD7 is a required scaffold of the ankle-link complex but is curated as a
    modifier and digenic contributor rather than as a primary causative locus: a
    heterozygous PDZD7 variant has been reported alongside variants in a second
    type-2 gene, and PDZD7 also modifies retinal disease in USH2A patients.
  evidence:
  - reference: PMID:20440071
    reference_title: "PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We validated the human genotypes using zebrafish, and our findings were consistent
      with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease
      modifier in patients with USH2A.
    explanation: Supports both the digenic contribution and the retinal-modifier role of PDZD7.
diagnosis:
- name: Audiologic and retinal functional evaluation
  description: >-
    Establish the clinical phenotype with subjective and electrophysiologic
    hearing and retinal testing. A sloping congenital loss with intact vestibular
    responses is the type-2 pattern.
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function."
    explanation: Establishes the clinical diagnostic route for type 2.
- name: Molecular genetic confirmation
  description: >-
    Identify biallelic pathogenic variants in one of the three type-2 genes.
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive."
    explanation: Establishes molecular confirmation for the three type-2 genes.
treatments:
- name: Hearing Aids
  description: >-
    Early hearing-aid fitting with speech training. Amplification rather than
    implantation is the usual first step here, because the type-2 loss is sloping
    and leaves useful low-frequency hearing.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid usage
  target_phenotypes:
  - preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Early fitting of hearing aids and speech training."
    explanation: GeneReviews recommends early hearing-aid fitting and speech training for type 2.
- name: Low-Vision Rehabilitation and Psychosocial Support
  description: >-
    Orientation and adaptive-skills training as vision declines, with vocational
    rehabilitation and mental-health support.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity"
    explanation: >-
      Establishes the progressive vision loss that low-vision rehabilitation
      addresses. The cited GeneReviews abstract does not itself state a low-vision
      rehabilitation recommendation for type 2, so this treatment is recorded on
      the disease course rather than on a quoted recommendation.
- name: Audiologic and Ophthalmologic Surveillance
  description: >-
    Annual multimodal retinal surveillance from age ten years, with audiologic
    follow-up for device users.
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual fundus photography, visual acuity, visual field, electroretinography, optical coherence tomography, and fundus autofluorescence from age ten years."
    explanation: Supports annual retinal surveillance from age ten in type 2.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal recessive recurrence risk, and in
    this entity also the possibility of a digenic PDZD7 contribution.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301515
    reference_title: "Usher Syndrome Type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child"
    explanation: Supports counseling for the autosomal recessive recurrence risk.
- name: Ultevursen (QR-421a)
  description: >-
    Investigational antisense oligonucleotide inducing skipping of USH2A exon 13,
    which carries the two recurrent pathogenic variants c.2299delG and c.2276G>T.
    Exon skipping is intended to produce a shortened usherin protein. Evaluated by
    intravitreal injection in the Phase 2b LUNA trial.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: USH2A
      term:
        id: hgnc:12601
        label: USH2A
    target_transcript: USH2A pre-mRNA
    target_exon: exon 13
  delivery_system:
    delivery_platform: UNFORMULATED
    targeting_ligand: UNCONJUGATED
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Ankle-Link Complex Assembly Failure
    treatment_effect: MODULATES
    description: >-
      In the USH2A exon-13 molecular subgroup, QR-421a induces exon 13 skipping
      upstream of the complex-assembly defect. This does not assert restored human
      complex function or clinical efficacy.
    evidence:
    - reference: PMID:33895329
      reference_title: Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in
        induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an
        Usher syndrome patient homozygous for the c.2299delG mutation.
      explanation: Supports splice modulation in patient-derived photoreceptor precursors, scoped to USH2A exon 13.
  evidence:
  - reference: PMID:33895329
    reference_title: Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in
      induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an
      Usher syndrome patient homozygous for the c.2299delG mutation.
    explanation: >-
      Patient-derived photoreceptor-precursor evidence supports QR-421a-mediated
      exon 13 skipping; it does not establish clinical efficacy.
  - reference: clinicaltrials:NCT06627179
    reference_title: A Two-Year Double-masked, Randomized, Sham-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this Phase 2b study is to evaluate the safety and tolerability of ultevursen administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.
    explanation: Registry record confirming Phase 2b evaluation, route, and molecular scope.
clinical_trials:
- name: NCT06627179
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Double-masked, randomized, sham-controlled Phase 2b LUNA study of intravitreal
    ultevursen in 81 participants with retinitis pigmentosa due to USH2A exon 13
    mutations. Registry status as recorded in the cached record retrieved
    2026-08-11; not re-checked for this split.
  target_phenotypes:
  - preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: clinicaltrials:NCT06627179
    reference_title: A Two-Year Double-masked, Randomized, Sham-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a multicenter Double-masked, Randomized, Sham-controlled study which will enroll 81 subjects."
    explanation: Establishes the LUNA design and planned enrollment.
animal_models:
- name: Pdzd7 interaction zebrafish model
  species: Zebrafish (Danio rerio)
  genotype: Pdzd7 knockdown alone and in combination with ush2a or gpr98 perturbation
  category: Knockdown interaction model
  description: >-
    Pdzd7 knockdown produces an Usher-like phenotype and worsens retinal cell
    death when combined with ush2a or gpr98 perturbation. It supports genetic
    interaction and retinal-modifier biology within the type-2 complex and does
    not reproduce the full human auditory-retinal disease.
  associated_phenotypes:
  - Retinal cell death
  modeled_mechanisms:
  - target: Photoreceptor Periciliary Membrane Complex Disruption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    limitations: >-
      Knockdown in zebrafish is a developmental perturbation and does not
      establish the magnitude or clinical course of PDZD7 modification in humans.
    description: >-
      Combined perturbation changes retinal cell survival and Gpr98 localization
      near the photoreceptor connecting cilium.
    evidence:
    - reference: PMID:20440071
      reference_title: "PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium."
      explanation: Supports the model's genetic-interaction and connecting-cilium readouts.
  evidence:
  - reference: PMID:20440071
    reference_title: "PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A."
    explanation: Supports use of the zebrafish experiment to test digenic and modifier hypotheses.
notes: >
  MONDO coverage of the type-2 subtype series. Each of the three locus subtypes now binds
  its own MONDO term - USH2A MONDO:0010169, USH2C MONDO:0011558, USH2D MONDO:0012662 - and
  MONDO makes all three children of MONDO:0016484, this entry's own term. MONDO:0024996,
  labelled "obsolete Usher syndrome, type 2b", is marked owl:deprecated with term-replaced-by
  MONDO:0011558, so USH2B and USH2C are one concept upstream and no separate row is needed.

  Two features of MONDO:0011558 are worth recording. It carries no causal-gene axiom in the
  release read on 2026-09-24, which is why a gene-keyed knowledge-graph comparison cannot see
  it even though ADGRV1 is the canonical USH2C gene. And its text definition describes a
  heterozygous GPR98 frameshift together with a heterozygous PDZD7 frameshift - the digenic
  observation - rather than the biallelic ADGRV1 disease the term is named for. This entry
  asserts the biallelic requirement instead, on the GeneReviews statement that names all
  three type-2 genes, now cited on the USH2C row as well as on the WHRN record and the
  USH2D row.

  PDZD7 is bound as a gene on the ankle-link assembly node even though its genetic record is
  a MODIFIER rather than a causative gene, because both of that node's cited snippets state
  that PDZD7 is required for complex formation. The binding records where the protein acts;
  the causal claim stays in the genetic record.

  Previous gene symbols, read from the HGNC build's synonym rows on 2026-09-24: ADGRV1 was
  reported as VLGR1 and is widely written GPR98, and HGNC carries both VLGR1 and
  "G protein-coupled receptor 98" as exact synonyms; WHRN was reported as DFNB31, which HGNC
  carries as "deafness, autosomal recessive 31".

  Reading the case fractions below: the meta-analysis denominator is all Usher syndrome, not
  type 2. Only the USH2A record carries a type-specific figure, because that is the only gene
  for which a type-2 denominator is stated in a source cited here.
review_notes: >-
  Created 2026-09-24 by splitting kb/disorders/Usher_Syndrome.yaml into four
  mechanism entities plus a grouping, per the decision recorded on issue #10822.

  The entity is defined by the ankle-link complex. The two facts that make it a
  distinct mechanism rather than a milder type 1 are that the complex is
  transient and developmental where the type-1 complex is mature and
  tension-bearing, and that its retinal counterpart is the periciliary membrane
  compartment rather than the calyceal-process adhesion belt.

  WHRN is held as a USH2D subtype rather than promoted, and the subtype
  description records that ClinGen curates it against a distinct MONDO term
  (MONDO:0012662) so that the decision is visible rather than flattened.

  PDZD7 is curated as a modifier in `genetic:` rather than as a fourth causative
  locus, which matches how the cited primary study frames it, even though it is a
  required structural member of the complex.

  The "Low-Vision Rehabilitation and Psychosocial Support" treatment carries
  evidence for the progressive vision loss it addresses rather than for the
  recommendation itself: the type-2 GeneReviews abstract does not state that
  recommendation, and the type-1 abstract that does cannot be quoted here without
  asserting it was said about type 2. The explanation says so rather than leaving
  the reader to assume a stronger source.

  Not curated here: the USH2A isolated-retinopathy branch (retinitis pigmentosa
  39). It is defined by ABSENT hearing loss, and FrequencyEnum has no excluded
  value until issue #10190 lands, so the subtype cannot state the thing that
  defines it. No per-entity prevalence is asserted: the 4-17 per 100,000 figure
  the lumped entry carried is for Usher syndrome as a whole, and the `Grouping`
  class has no prevalence slot, so that figure is carried in the grouping's prose.
📚

References & Deep Research

References

15
PMID:20301515
Usher Syndrome Type II.
No top-level findings curated for this source.
PMID:24239741
Usher protein functions in hair cells and photoreceptors.
No top-level findings curated for this source.
PMID:25406310
Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.
No top-level findings curated for this source.
PMID:32995707
Usher syndrome: clinical features, molecular genetics and advancing therapeutics.
No top-level findings curated for this source.
PMID:33193648
Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy.
No top-level findings curated for this source.
PMID:33895329
Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations.
No top-level findings curated for this source.
PMID:35353227
The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification.
No top-level findings curated for this source.
PMID:36964137
Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.
No top-level findings curated for this source.
PMID:20440071
PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome.
No top-level findings curated for this source.
No top-level findings curated for this source.
clinicaltrials:NCT06627179
A Two-Year Double-masked, Randomized, Sham-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
No top-level findings curated for this source.
PMID:30531642
Genetics of Usher Syndrome: New Insights From a Meta-analysis.
No top-level findings curated for this source.
PMID:9624053
Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.
No top-level findings curated for this source.
PMID:14740321
Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II.
No top-level findings curated for this source.
PMID:17171570
A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss.
No top-level findings curated for this source.