Usher Syndrome Type 1

Mendelian MONDO:0010168 Pathograph 21 Show in embeddings browser Inherited retinal dystrophy Sensorineural hearing loss

Usher syndrome type 1 is the mechanism entity in which biallelic loss of a component of the stereocilia upper tip-link density (UTLD) complex - myosin VIIa (MYO7A), harmonin (USH1C), SANS (USH1G), cadherin-23 (CDH23) and protocadherin-15 (PCDH15) - produces congenital profound sensorineural hearing loss, absent vestibular function, and adolescent-onset retinitis pigmentosa. The defining lesion is a tension-bearing complex of the MATURE hair bundle, in which a myosin motor cluster anchored by harmonin and SANS holds the cadherin-23/protocadherin-15 tip link under resting tension so that bundle deflection gates the mechanotransduction channel. This is a different assembly, in a different developmental window, from the transient ankle-link complex of Usher syndrome type 2, and clarin-1 (type 3) belongs to neither. In the retina the same five proteins form a conserved network at the calyceal processes - microvillus-like projections collaring the base of the photoreceptor outer segment in human, macaque and frog. This is NOT the periciliary membrane compartment that carries the type-2 retinal mechanism, and it is the reason the classical mouse models are deaf without retinal degeneration: mice have no calyceal processes at all. The numbered clinical type is retained as the entry label because it is the identity ClinGen and MONDO both curate at, but the entity is defined by the complex rather than by the clinical typing, which is an imperfect proxy - a CLRN1 (type 3) family has been reported as clinically diagnosable as type 1.

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1
Inheritance
5
Pathophys.
7
Phenotypes
1
Gaps
21
Pathograph
6
Genes
8
Medical Actions
6
Subtypes
1
Trials
17
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33193648 SUPPORT Human Clinical
"Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance."
Confirms the autosomal recessive inheritance pattern shared across the Usher entities.
◆

Subtypes

6
Usher syndrome type 1B (MYO7A) MONDO:0700087
MYO7A hgnc:7606 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYO7A (hgnc:7606). hgnc:7606 is a gene from the HUGO Gene Nomenclature Committee.
The most common type-1 locus, accounting for more than half of type-1 cases. Myosin VIIa is the motor element of the upper tip-link density complex. USH1B is the subtype with an active retinal gene-therapy programme (dual-AAV MYO7A), which is what makes the choice of MYO7A isoform to deliver a live therapeutic design question rather than an academic one. Named for the locus rather than the gene on purpose: USH1C and USH1G are simultaneously locus designations and HGNC gene symbols, so a gene-symbol naming convention would be ambiguous for two of the five subtypes.
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."
Documents MYO7A as the major type-1 locus, accounting for more than 50% of type 1.
PMID:7870171 SUPPORT Human Clinical
"Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B."
Primary report assigning the USH1B locus to MYO7A, which is the gene-to-locus assignment this row binds to MONDO:0700087.
Usher syndrome type 1C (USH1C, harmonin) MONDO:0010171
USH1C hgnc:12597 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in USH1C (hgnc:12597). hgnc:12597 is a gene from the HUGO Gene Nomenclature Committee.
Harmonin is the scaffold of the upper tip-link density complex. It is the one type-1 protein that genuinely spans two of the Usher entities: harmonin PDZ1 also binds the C-terminal PDZ-binding motifs of USH2A and ADGRV1, so harmonin is a deliberate physical bridge between the type-1 and type-2 networks rather than an annotation artifact. It is included here because the tension-bearing tip-link role is the one whose loss produces the type-1 presentation.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms USH1C as one of the five established type-1 genes.
PMID:10973247 SUPPORT Human Clinical
"We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas."
Primary report assigning the USH1C locus to the gene encoding harmonin, which is the gene-to-locus assignment this row binds to MONDO:0010171.
Usher syndrome type 1D (CDH23) MONDO:0010984
CDH23 hgnc:13733 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CDH23 (hgnc:13733). hgnc:13733 is a gene from the HUGO Gene Nomenclature Committee.
Cadherin-23 forms the upper half of the tip link.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms CDH23 as one of the five established type-1 genes.
PMID:11138009 SUPPORT Human Clinical
"Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype."
Primary report assigning the USH1D locus to CDH23, which is the gene-to-locus assignment this row binds to MONDO:0010984 - the term for which MONDO itself records no causal gene.
Usher syndrome type 1F (PCDH15) MONDO:0011186
PCDH15 hgnc:14674 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PCDH15 (hgnc:14674). hgnc:14674 is a gene from the HUGO Gene Nomenclature Committee.
Protocadherin-15 forms the lower half of the tip link, pairing with cadherin-23.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms PCDH15 as one of the five established type-1 genes.
PMID:11398101 SUPPORT Human Clinical
"Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F."
Primary report assigning the USH1F locus to PCDH15, which is the gene-to-locus assignment this row binds to MONDO:0011186.
Usher syndrome type 1G (USH1G, SANS) MONDO:0011748
USH1G hgnc:16356 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in USH1G (hgnc:16356). hgnc:16356 is a gene from the HUGO Gene Nomenclature Committee.
SANS is the third member of the tripartite MYO7A/SANS/harmonin-b core of the upper tip-link density.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms USH1G as one of the five established type-1 genes.
PMID:12588794 SUPPORT Human Clinical
"These results demonstrate that SANS underlies USH1G."
Primary report assigning the USH1G locus to the SANS gene, approved symbol USH1G, which is the gene-to-locus assignment this row binds to MONDO:0011748.
Usher syndrome type 1D/F (digenic CDH23 + PCDH15) MONDO:0100050
CDH23 hgnc:13733 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CDH23 (hgnc:13733). hgnc:13733 is a gene from the HUGO Gene Nomenclature Committee. PCDH15 hgnc:14674 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PCDH15 (hgnc:14674). hgnc:14674 is a gene from the HUGO Gene Nomenclature Committee.
A type-1 phenotype in which single heterozygous variants at the two tip-link cadherin loci act together, rather than biallelic variants at either. It is a separate row from USH1D and USH1F because the inheritance claim differs: neither locus is biallelic, so those two rows do not describe it. The corresponding mouse cross is hearing-impaired as a double heterozygote while age-matched single heterozygotes are not, which is what establishes an interaction rather than simple carriage.
Show evidence (2 references)
PMID:15537665 SUPPORT Human Clinical
"In humans, we also have obtained evidence for a digenic inheritance of a USH1 phenotype in three unrelated families with mutations in CDH23 and PCDH15."
Primary human evidence for the digenic CDH23-PCDH15 type-1 phenotype this row records.
PMID:15537665 SUPPORT Model Organism
"Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls."
The mouse double-heterozygote result that establishes the interaction rather than simple heterozygous carriage.
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Discussions and Knowledge Gaps

1
Can a mouse model report on the type-1 retinal mechanism at all, given that mice have no calyceal processes?
HUMAN MODEL MISMATCH ush1_mouse_lacks_calyceal_processes
Attached to
pathophysiology#Photoreceptor Calyceal Process Network Disruption
The classical type-1 mouse models are deaf without retinal degeneration, and the usual explanation has been species differences in where individual proteins are expressed. A structural explanation covers all five genes at once: the mouse photoreceptor lacks calyceal processes entirely, so the structure the type-1 protein network builds in human, macaque and frog does not exist in the model organism. That makes the absent retinal phenotype an expected consequence of the model rather than evidence against the mechanism, and it means a negative retinal result in mouse carries very little weight for this entity. This bears directly on preclinical efficacy testing for MYO7A gene therapy: a mouse retina cannot report restoration of a structure it never had.
Show evidence (1 reference)
PMID:23045546 SUPPORT Model Organism
"By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface."
States the structural absence that makes the mouse retina uninformative for this mechanism.
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Pathophysiology

5
Hair Cell Mechanotransduction Failure
Cochlear and vestibular hair cells cannot convert bundle deflection into a receptor potential. Because the UTLD complex is required in the mature bundle and from development onward, the failure is present at birth, producing congenital profound hearing loss and complete vestibular areflexia rather than a progressive postlingual course.
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
Congenital Sensorineural Hearing Loss Transduction failure present from birth produces congenital bilateral profound sensorineural hearing loss.
Vestibular Areflexia Loss of vestibular hair cell transduction abolishes vestibular responses.
Delayed Motor Development Absent vestibular input delays postural control and independent walking.
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 tip-link destabilization to inhibited mechanosensory transduction.
Photoreceptor Calyceal Process Network Disruption
In human, macaque and frog photoreceptors the five type-1 proteins colocalize at the interface between the inner and outer segments and between the microvillus-like calyceal processes and the basolateral outer segment. Loss of a network component is expected to destabilize that adhesion belt and the structural relationship it maintains between the calyceal processes and the outer segment. This is a different subcellular compartment from the periciliary membrane complex that carries the type-2 retinal mechanism, which is why a single "connecting cilium dysfunction" node cannot serve both entities.
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. retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
MYO7A hgnc:7606 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO7A (hgnc:7606). hgnc:7606 is a gene from the HUGO Gene Nomenclature Committee. USH1C hgnc:12597 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves USH1C (hgnc:12597). hgnc:12597 is a gene from the HUGO Gene Nomenclature Committee. CDH23 hgnc:13733 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDH23 (hgnc:13733). hgnc:13733 is a gene from the HUGO Gene Nomenclature Committee. PCDH15 hgnc:14674 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PCDH15 (hgnc:14674). hgnc:14674 is a gene from the HUGO Gene Nomenclature Committee. USH1G hgnc:16356 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves USH1G (hgnc:16356). hgnc:16356 is a gene from the HUGO Gene Nomenclature Committee.
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.
Downstream
Photoreceptor Degeneration Loss of the calyceal-process adhesion network destabilizes outer-segment architecture and is followed by progressive photoreceptor loss.
Show evidence (2 references)
PMID:23045546 SUPPORT Model Organism
"This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards."
Establishes the conserved calyceal-process network as the type-1 retinal structure.
PMID:23045546 SUPPORT Model Organism
"We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones."
Sources the colocalization of all five type-1 proteins at the calyceal-process interface, which is the basis for binding the five genes to this node.
Photoreceptor Degeneration
Progressive rod-then-cone degeneration, clinically adolescent-onset 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.
Constricted Visual Fields Peripheral rod loss constricts the visual field.
Night Blindness Early rod loss produces nyctalopia.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
Establishes the rod-then-cone progression in type 1.
⬡

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 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Ear 2
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:20301442 SUPPORT Human Clinical
"Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
Confirms congenital bilateral profound sensorineural hearing loss in type 1.
Vestibular Areflexia HP:0008568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vestibular areflexia (HP:0008568). HP:0008568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
Confirms vestibular areflexia as a defining type-1 feature.
Eye 4
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:20301442 SUPPORT Human Clinical
"Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
Establishes adolescent-onset retinitis pigmentosa in type 1.
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:20301442 SUPPORT Human Clinical
"RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
Documents progressive visual-field constriction from rod loss.
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:32995707 SUPPORT Human Clinical
"Typically, the first presenting symptom is night blindness (nyctalopia) with progressive visual field loss beginning in the mid-periphery caused by rod photoreceptor degeneration."
Documents nyctalopia as the first presenting retinal symptom.
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 (2 references)
PMID:35353227 SUPPORT Model Organism
"As in the inner ear, USH protein defects cause diverse phenotypic abnormalities in the retina, including decreased electroretinogram responses (ERGs), probably due to misshapen photoreceptor disks"
Model evidence supports decreased ERG responses as a readout of Usher retinal dysfunction.
PMID:20301442 SUPPORT Human Clinical
"The diagnosis of USH1 is established in a proband with characteristic findings on electrophysiologic and subjective tests of hearing and retinal function."
Human support that retinal electrophysiology is part of establishing the type-1 diagnosis. It does not specify a waveform, so the direction of the abnormality rests on the model evidence above.
Nervous System 1
Delayed Motor Development Delayed gross motor development HP:0002194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed gross motor development (HP:0002194). HP:0002194 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35353227 SUPPORT REVIEW SYNTHESIS Other
"Many USH1 patients do not begin to walk before the age of 18 months, and vestibular areflexia is responsible for the delayed motor development observed in these patients"
Supports delayed walking as a vestibular consequence in type 1.
🧬

Genetic Associations

6
MYO7A (Causative)
Gene: MYO7A hgnc:7606 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYO7A (hgnc:7606). hgnc:7606 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_1e897a2f-d4cf-4e13-85d8-f37405a09b18-2018-06-28T160000.000Z SUPPORT Other
"MYO7A | HGNC:7606 | Usher syndrome type 1 | MONDO:0010168 | AR | Definitive | SOP5 | Hearing Loss Gene Curation Expert Panel"
ClinGen classifies the MYO7A-type 1 gene-disease relationship as Definitive against this entry's own MONDO term.
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 MYO7A as the majority type-1 locus.
USH1C (Causative)
Gene: USH1C hgnc:12597 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is USH1C (hgnc:12597). hgnc:12597 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms USH1C as an established type-1 gene.
CDH23 (Causative)
Gene: CDH23 hgnc:13733 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CDH23 (hgnc:13733). hgnc:13733 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms CDH23 as an established type-1 gene.
PCDH15 (Causative)
Gene: PCDH15 hgnc:14674 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PCDH15 (hgnc:14674). hgnc:14674 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms PCDH15 as an established type-1 gene.
USH1G (Causative)
Gene: USH1G hgnc:16356 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is USH1G (hgnc:16356). hgnc:16356 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Confirms USH1G as an established type-1 gene.
CIB2 (Not causative)
Gene: CIB2 hgnc:24579 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CIB2 (hgnc:24579). hgnc:24579 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (1 reference)
CGGV:assertion_95709038-78a4-4043-a054-9cbe245d2588-2019-02-19T170000.000Z REFUTE Other
"CIB2 | HGNC:24579 | Usher syndrome type 1 | MONDO:0010168 | AR | Refuted | SOP6 | Hearing Loss Gene Curation Expert Panel"
ClinGen refutes CIB2 as a cause of Usher syndrome type 1.
💊

Medical Actions

8
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Cochlear implantation should be considered as young as medically feasible, typically before age one year. The profound congenital loss of type 1 makes this the primary auditory intervention, in contrast to type 2 where hearing aids are the usual first step.
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:20301442 SUPPORT Human Clinical
"Cochlear implantation should be considered as young as medically feasible, typically before age one year."
GeneReviews recommends early cochlear implantation for the profound hearing loss of type 1.
Vestibular Physical Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physical therapy and vestibular rehabilitation for the areflexia and imbalance of type 1, beginning in childhood and continuing throughout the disease course.
Target Phenotypes: Vestibular areflexia HP:0008568 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Vestibular areflexia (HP:0008568). HP:0008568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Physical therapy is recommended to manage vestibular dysfunction and imbalance throughout the disease course"
GeneReviews recommends physical therapy for the vestibular dysfunction of type 1.
Speech and Multimodal Communication Support
Platform: Behavioral / lifestyle
Pair hearing technology with timely audioverbal therapy where auditory communication is pursued, and offer sign language from infancy so a robust communication modality exists before and alongside devices.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Timely audioverbal therapy following cochlear implantation is required for the development of speech."
Supports timely audioverbal therapy after implantation.
PMID:20301442 SUPPORT Human Clinical
"Sign language is recommended as early as birth to stimulate communication and language development prior to hearing aids and/or cochlear implants and is used throughout life as an additional means of communication when cochlear implants are not working or accessible, or as a primary means of..."
Supports early and lifelong access to sign language rather than device-only communication.
Low-Vision Rehabilitation and Psychosocial Support
Platform: Behavioral / lifestyle
Orientation and adaptive-skills training as vision declines, with school or vocational rehabilitation and recurring mental-health support for affected people and families.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Skills for adjusting to progressive vision loss can be accessed through school, vocational rehabilitation, or training programs."
Supports adaptive and vocational rehabilitation for progressive vision loss.
PMID:20301442 SUPPORT Human Clinical
"Counseling for individuals living with USH1 and family members is recommended to manage mental health throughout the disease course, beginning in childhood and again as vision loss progresses."
Supports longitudinal mental-health counseling for affected people and families.
Audiologic and Ophthalmologic Surveillance
Annual audiologic surveillance for device users and annual multimodal retinal surveillance beginning before visual symptoms.
Show evidence (2 references)
PMID:20301442 SUPPORT Human Clinical
"Annual audiometry and tympanometry in those with cochlear implants or hearing aids to assure adequate auditory stimulation."
Supports annual audiologic surveillance for device users.
PMID:20301442 SUPPORT Human Clinical
"Annual ophthalmologic evaluation with fundus photography, visual acuity, visual field testing, electroretinography, optical coherence tomography, and fundus autofluorescence prior to the onset of visual manifestations."
Supports annual multimodal ophthalmologic surveillance before visual manifestations.
Smoking Avoidance and Sunlight Protection
Platform: Behavioral / lifestyle
Counsel against tobacco smoking and recommend sunglasses and a cap to limit bright-light exposure as modifiable precautions for retinitis pigmentosa.
Target Phenotypes: Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Exposure to bright sunlight and smoking tobacco can accelerate progression of RP. Refrain from smoking and avoid exposing eyes to sunlight by wearing sunglasses and a cap."
Supports smoking avoidance and sunlight protection as precautions intended to limit RP progression.
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 informs reproductive decision-making.
Show evidence (1 reference)
PMID:33193648 SUPPORT Human Clinical
"Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance."
Supports counseling for the autosomal recessive recurrence risk.
Dual-AAV MYO7A Retinal Gene Therapy
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
Investigational subretinal dual-AAV8 MYO7A gene replacement (AAVB-081) for USH1B retinitis pigmentosa. The dual-vector design exists because the MYO7A coding sequence exceeds the packaging capacity of a single AAV, which is what makes the choice of which MYO7A isoform to deliver a design decision with consequences rather than a detail.
Target Phenotypes: Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06591793 SUPPORT Human Clinical
"The purpose of the 081-101 study is to evaluate the safety and tolerability of a single subretinal injection of AAVB-081 in USH1B patients with retinitis pigmentosa due to a mutation in the MYO7A gene."
Establishes intervention, route, subtype scope, and MYO7A molecular eligibility.
🔬

Diagnosis

2
Audiologic, vestibular and retinal functional evaluation
Establish the clinical phenotype with subjective and electrophysiologic hearing and retinal testing. Vestibular testing carries particular weight here because areflexia is present from infancy, long before the retinal phenotype.
Results: Congenital profound hearing loss with absent vestibular responses distinguishes type 1 from type 2 and type 3 before retinitis pigmentosa is detectable.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"The diagnosis of USH1 is established in a proband with characteristic findings on electrophysiologic and subjective tests of hearing and retinal function."
Establishes combined hearing and retinal functional testing as the clinical diagnostic route.
Molecular genetic confirmation
Identify biallelic pathogenic variants in one of the five type-1 genes.
Show evidence (1 reference)
PMID:20301442 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Establishes molecular confirmation for the five type-1 genes.
🔬

Clinical Trials

1
NCT06591793 PHASE_I RECRUITING
Open-label Phase 1/2 dose-escalation study of a single subretinal injection of dual-AAV8 MYO7A gene therapy (AAVB-081) in people with USH1B retinitis pigmentosa. The schema records this combined Phase 1/2 study as PHASE_I. 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:NCT06591793 SUPPORT Human Clinical
"The purpose of the 081-101 study is to evaluate the safety and tolerability of a single subretinal injection of AAVB-081 in USH1B patients with retinitis pigmentosa due to a mutation in the MYO7A gene."
Registry record establishing the USH1B gene-therapy trial.
{ }

Source YAML

click to show 
name: Usher Syndrome Type 1
creation_date: "2026-09-24T00:00:00Z"
category: Mendelian
synonyms:
- USH1
- Usher syndrome type I
- Usher syndrome type 1
description: >
  Usher syndrome type 1 is the mechanism entity in which biallelic loss of a
  component of the stereocilia upper tip-link density (UTLD) complex - myosin
  VIIa (MYO7A), harmonin (USH1C), SANS (USH1G), cadherin-23 (CDH23) and
  protocadherin-15 (PCDH15) - produces congenital profound sensorineural hearing
  loss, absent vestibular function, and adolescent-onset retinitis pigmentosa.
  The defining lesion is a tension-bearing complex of the MATURE hair bundle, in
  which a myosin motor cluster anchored by harmonin and SANS holds the
  cadherin-23/protocadherin-15 tip link under resting tension so that bundle
  deflection gates the mechanotransduction channel. This is a different assembly,
  in a different developmental window, from the transient ankle-link complex of
  Usher syndrome type 2, and clarin-1 (type 3) belongs to neither.

  In the retina the same five proteins form a conserved network at the calyceal
  processes - microvillus-like projections collaring the base of the photoreceptor
  outer segment in human, macaque and frog. This is NOT the periciliary membrane
  compartment that carries the type-2 retinal mechanism, and it is the reason the
  classical mouse models are deaf without retinal degeneration: mice have no
  calyceal processes at all.

  The numbered clinical type is retained as the entry label because it is the
  identity ClinGen and MONDO both curate at, but the entity is defined by the
  complex rather than by the clinical typing, which is an imperfect proxy - a
  CLRN1 (type 3) family has been reported as clinically diagnosable as type 1.
disease_term:
  preferred_term: Usher syndrome type 1
  term:
    id: MONDO:0010168
    label: Usher syndrome type 1
parents:
- Inherited retinal dystrophy
- Sensorineural hearing loss
references:
- reference: PMID:20301442
  title: "Usher Syndrome Type I."
  tags:
  - GeneReviews
- reference: PMID:21709241
  title: Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.
- reference: PMID:23045546
  title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
- reference: PMID:24239741
  title: Usher protein functions in hair cells and photoreceptors.
- 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:35353227
  title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
- reference: CGGV:assertion_1e897a2f-d4cf-4e13-85d8-f37405a09b18-2018-06-28T160000.000Z
  title: "MYO7A / Usher syndrome type 1 (Definitive)"
- reference: CGGV:assertion_95709038-78a4-4043-a054-9cbe245d2588-2019-02-19T170000.000Z
  title: "CIB2 / Usher syndrome type 1 (Refuted)"
- reference: clinicaltrials:NCT06591793
  title: A Phase 1/2 Multicenter, Open-label, Dose Escalation, Safety and Efficacy Study of Subretinal Administration of Dual AAV8.MYO7A, AAVB-081 in Subjects With Usher Syndrome Type IB (USH1B) Retinitis Pigmentosa
- reference: PMID:15537665
  title: Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans.
- reference: PMID:30531642
  title: "Genetics of Usher Syndrome: New Insights From a Meta-analysis."
- reference: PMID:7870171
  title: Defective myosin VIIA gene responsible for Usher syndrome type 1B.
- reference: PMID:10973247
  title: "A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C."
- reference: PMID:11138009
  title: "Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D."
- reference: PMID:11398101
  title: Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.
- reference: PMID:12588794
  title: "Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin."
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33193648
    reference_title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance."
    explanation: Confirms the autosomal recessive inheritance pattern shared across the Usher entities.
has_subtypes:
- name: USH1B
  display_name: Usher syndrome type 1B (MYO7A)
  subtype_term:
    preferred_term: Usher syndrome type 1B
    term:
      id: MONDO:0700087
      label: Usher syndrome type 1B
  description: >-
    The most common type-1 locus, accounting for more than half of type-1 cases.
    Myosin VIIa is the motor element of the upper tip-link density complex. USH1B
    is the subtype with an active retinal gene-therapy programme (dual-AAV MYO7A),
    which is what makes the choice of MYO7A isoform to deliver a live therapeutic
    design question rather than an academic one.

    Named for the locus rather than the gene on purpose: USH1C and USH1G are
    simultaneously locus designations and HGNC gene symbols, so a gene-symbol
    naming convention would be ambiguous for two of the five subtypes.
  genes:
  - preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  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: Documents MYO7A as the major type-1 locus, accounting for more than 50% of type 1.
  - reference: PMID:7870171
    reference_title: Defective myosin VIIA gene responsible for Usher syndrome type 1B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B."
    explanation: >-
      Primary report assigning the USH1B locus to MYO7A, which is the gene-to-locus
      assignment this row binds to MONDO:0700087.
- name: USH1C
  display_name: Usher syndrome type 1C (USH1C, harmonin)
  subtype_term:
    preferred_term: Usher syndrome type 1C
    term:
      id: MONDO:0010171
      label: Usher syndrome type 1C
  description: >-
    Harmonin is the scaffold of the upper tip-link density complex. It is the one
    type-1 protein that genuinely spans two of the Usher entities: harmonin PDZ1
    also binds the C-terminal PDZ-binding motifs of USH2A and ADGRV1, so harmonin
    is a deliberate physical bridge between the type-1 and type-2 networks rather
    than an annotation artifact. It is included here because the tension-bearing
    tip-link role is the one whose loss produces the type-1 presentation.
  genes:
  - preferred_term: USH1C
    term:
      id: hgnc:12597
      label: USH1C
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms USH1C as one of the five established type-1 genes.
  - reference: PMID:10973247
    reference_title: "A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas."
    explanation: >-
      Primary report assigning the USH1C locus to the gene encoding harmonin, which is the
      gene-to-locus assignment this row binds to MONDO:0010171.
- name: USH1D
  display_name: Usher syndrome type 1D (CDH23)
  subtype_term:
    preferred_term: Usher syndrome type 1D
    term:
      id: MONDO:0010984
      label: Usher syndrome type 1D
  description: >-
    Cadherin-23 forms the upper half of the tip link.
  genes:
  - preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms CDH23 as one of the five established type-1 genes.
  - reference: PMID:11138009
    reference_title: "Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype."
    explanation: >-
      Primary report assigning the USH1D locus to CDH23, which is the gene-to-locus
      assignment this row binds to MONDO:0010984 - the term for which MONDO itself records
      no causal gene.
- name: USH1F
  display_name: Usher syndrome type 1F (PCDH15)
  subtype_term:
    preferred_term: Usher syndrome type 1F
    term:
      id: MONDO:0011186
      label: Usher syndrome type 1F
  description: >-
    Protocadherin-15 forms the lower half of the tip link, pairing with
    cadherin-23.
  genes:
  - preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms PCDH15 as one of the five established type-1 genes.
  - reference: PMID:11398101
    reference_title: Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F."
    explanation: >-
      Primary report assigning the USH1F locus to PCDH15, which is the gene-to-locus
      assignment this row binds to MONDO:0011186.
- name: USH1G
  display_name: Usher syndrome type 1G (USH1G, SANS)
  subtype_term:
    preferred_term: Usher syndrome type 1G
    term:
      id: MONDO:0011748
      label: Usher syndrome type 1G
  description: >-
    SANS is the third member of the tripartite MYO7A/SANS/harmonin-b core of the
    upper tip-link density.
  genes:
  - preferred_term: USH1G
    term:
      id: hgnc:16356
      label: USH1G
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms USH1G as one of the five established type-1 genes.
  - reference: PMID:12588794
    reference_title: "Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results demonstrate that SANS underlies USH1G."
    explanation: >-
      Primary report assigning the USH1G locus to the SANS gene, approved symbol USH1G,
      which is the gene-to-locus assignment this row binds to MONDO:0011748.
- name: USH1DF
  display_name: Usher syndrome type 1D/F (digenic CDH23 + PCDH15)
  subtype_term:
    preferred_term: Usher syndrome, type 1D/F
    term:
      id: MONDO:0100050
      label: Usher syndrome, type 1D/F
  genes:
  - preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  - preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  description: >-
    A type-1 phenotype in which single heterozygous variants at the two tip-link cadherin
    loci act together, rather than biallelic variants at either. It is a separate row from
    USH1D and USH1F because the inheritance claim differs: neither locus is biallelic, so
    those two rows do not describe it. The corresponding mouse cross is hearing-impaired
    as a double heterozygote while age-matched single heterozygotes are not, which is what
    establishes an interaction rather than simple carriage.
  evidence:
  - reference: PMID:15537665
    reference_title: Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, we also have obtained evidence for a digenic inheritance of a USH1 phenotype in three unrelated families with mutations in CDH23 and PCDH15."
    explanation: Primary human evidence for the digenic CDH23-PCDH15 type-1 phenotype this row records.
  - reference: PMID:15537665
    reference_title: Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls."
    explanation: >-
      The mouse double-heterozygote result that establishes the interaction rather than
      simple heterozygous carriage.
pathophysiology:
- name: Upper Tip-Link Density Complex Disruption
  genes:
  - preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  - preferred_term: USH1C
    term:
      id: hgnc:12597
      label: USH1C
  - preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  - preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  - preferred_term: USH1G
    term:
      id: hgnc:16356
      label: USH1G
  subtypes:
  - USH1B
  - USH1C
  - USH1D
  - USH1F
  - USH1G
  description: >-
    Biallelic loss of myosin VIIa, harmonin, SANS, cadherin-23 or
    protocadherin-15 disrupts the upper tip-link density (UTLD), the
    tension-bearing assembly at the insertion point of the tip link into the
    taller stereocilium. In the accepted model a cluster of myosin motors at the
    UTLD holds the tip link under resting tension; myosin VIIa and SANS are
    localized there, which is what places these Usher proteins in
    mechanotransduction rather than only in bundle morphogenesis.

    This is the mature-bundle complex. It is deliberately distinguished from the
    transient ankle-link complex that carries the type-2 mechanism, which is
    present in developing stereocilia and absent from mature ones.
  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: Hair Bundle Cohesion and Tip-Link Tension Failure
    description: >-
      Loss of a UTLD component removes the anchoring or tensioning element of the
      tip link, so bundle cohesion and resting tip-link tension are not maintained.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21709241
      reference_title: Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "In the most accepted model for hair cell mechanotransduction, a cluster of myosin motors located at the stereocilia upper tip-link density (UTLD) keeps the tip-link under tension at rest."
      explanation: >-
        States the tension-bearing role of the UTLD myosin cluster. Marked
        BACKGROUND: this is the paper's opening statement of the accepted model,
        not the localization result the study itself produced.
  - target: Photoreceptor Calyceal Process Network Disruption
    description: >-
      The same five proteins form a network at the photoreceptor calyceal
      processes, so the retinal branch is a parallel consequence of the same
      molecular lesion rather than a sequel to the cochlear one.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23045546
      reference_title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards."
      explanation: Establishes that the same type-1 proteins form a conserved network at the calyceal processes.
  evidence:
  - reference: PMID:21709241
    reference_title: Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "In the most accepted model for hair cell mechanotransduction, a cluster of myosin motors located at the stereocilia upper tip-link density (UTLD) keeps the tip-link under tension at rest."
    explanation: >-
      Identifies the UTLD as the tension-bearing complex whose components define
      this entity. Marked BACKGROUND: the sentence states the accepted model the
      paper works from, not its own finding.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: >-
      Sources the five genes bound to this node as the established type-1 gene set; the
      item above sources the complex they act in.
- name: Hair Bundle Cohesion and Tip-Link Tension Failure
  genes:
  - preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  - preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  description: >-
    Without an intact UTLD the cadherin-23/protocadherin-15 tip link is not
    correctly anchored or tensioned, and the graded-height cohesion of the
    stereocilia bundle is lost. Because the tip link gates the transduction
    channel directly, this is a failure of the transduction apparatus itself, not
    a downstream degenerative change.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  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: >-
      Disrupted tip-links abolish the deflection-gated mechanotransduction
      current.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24239741
      reference_title: "Usher protein functions in hair cells and photoreceptors."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed."
      explanation: Links disruption of the mature-bundle tip-link complex to mechanotransduction failure and deafness.
  evidence:
  - reference: PMID:24239741
    reference_title: "Usher protein functions in hair cells and photoreceptors."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed."
    explanation: Establishes that cadherin-23 and protocadherin-15 form the mature tip link.
- name: Hair Cell Mechanotransduction Failure
  description: >-
    Cochlear and vestibular hair cells cannot convert bundle deflection into a
    receptor potential. Because the UTLD complex is required in the mature bundle
    and from development onward, the failure is present at birth, producing
    congenital profound hearing loss and complete vestibular areflexia rather
    than a progressive postlingual course.
  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: Congenital Sensorineural Hearing Loss
    description: >-
      Transduction failure present from birth produces congenital bilateral
      profound sensorineural hearing loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301442
      reference_title: "Usher Syndrome Type I."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
      explanation: Establishes congenital profound sensorineural hearing loss as the type-1 auditory presentation.
  - target: Vestibular Areflexia
    description: >-
      Loss of vestibular hair cell transduction abolishes vestibular responses.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301442
      reference_title: "Usher Syndrome Type I."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
      explanation: Establishes vestibular areflexia as a defining type-1 feature.
  - target: Delayed Motor Development
    description: >-
      Absent vestibular input delays postural control and independent walking.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absent vestibular input
    - impaired postural and balance control in infancy
    evidence:
    - reference: PMID:35353227
      reference_title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Many USH1 patients do not begin to walk before the age of 18 months, and vestibular areflexia is responsible for the delayed motor development observed in these patients"
      explanation: Attributes the delayed motor development of type 1 to vestibular areflexia.
  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 tip-link destabilization to inhibited mechanosensory transduction.
- name: Photoreceptor Calyceal Process Network Disruption
  genes:
  - preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  - preferred_term: USH1C
    term:
      id: hgnc:12597
      label: USH1C
  - preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  - preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  - preferred_term: USH1G
    term:
      id: hgnc:16356
      label: USH1G
  subtypes:
  - USH1B
  - USH1C
  - USH1D
  - USH1F
  - USH1G
  description: >-
    In human, macaque and frog photoreceptors the five type-1 proteins colocalize
    at the interface between the inner and outer segments and between the
    microvillus-like calyceal processes and the basolateral outer segment. Loss of
    a network component is expected to destabilize that adhesion belt and the
    structural relationship it maintains between the calyceal processes and the
    outer segment.

    This is a different subcellular compartment from the periciliary membrane
    complex that carries the type-2 retinal mechanism, which is why a single
    "connecting cilium dysfunction" node cannot serve both entities.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  downstream:
  - target: Photoreceptor Degeneration
    description: >-
      Loss of the calyceal-process adhesion network destabilizes outer-segment
      architecture and is followed by progressive photoreceptor loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23045546
      reference_title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones."
      explanation: >-
        Localizes all five type-1 proteins to the calyceal-process interface in a
        primate retina. The step from that localization to degeneration is not
        itself demonstrated here, so the link is recorded with unknown
        intermediates.
  evidence:
  - reference: PMID:23045546
    reference_title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards."
    explanation: Establishes the conserved calyceal-process network as the type-1 retinal structure.
  - reference: PMID:23045546
    reference_title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones."
    explanation: >-
      Sources the colocalization of all five type-1 proteins at the calyceal-process
      interface, which is the basis for binding the five genes to this node.
- name: Photoreceptor Degeneration
  description: >-
    Progressive rod-then-cone degeneration, clinically adolescent-onset 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:20301442
      reference_title: "Usher Syndrome Type I."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
      explanation: Defines type-1 retinitis pigmentosa as adolescent-onset progressive photoreceptor degeneration.
  - target: Constricted Visual Fields
    description: Peripheral rod loss constricts the visual field.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301442
      reference_title: "Usher Syndrome Type I."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
      explanation: Links rod loss to progressive visual-field constriction.
  - target: Night Blindness
    description: Early rod loss produces nyctalopia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32995707
      reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Typically, the first presenting symptom is night blindness (nyctalopia) with progressive visual field loss beginning in the mid-periphery caused by rod photoreceptor degeneration."
      explanation: Attributes nyctalopia to rod photoreceptor degeneration.
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
    explanation: Establishes the rod-then-cone progression in type 1.
phenotypes:
- category: Auditory
  name: Congenital Sensorineural Hearing Loss
  description: >-
    Congenital bilateral profound sensorineural hearing loss is the defining
    auditory presentation of type 1 and is what separates it clinically from the
    sloping congenital loss of type 2 and the progressive postlingual loss of
    type 3.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
    explanation: Confirms congenital bilateral profound sensorineural hearing loss in type 1.
- category: Vestibular
  name: Vestibular Areflexia
  description: >-
    Absent vestibular responses. Unlike type 2, where vestibular function is
    intact or variable, areflexia is constant in type 1 and is the earliest
    clinically detectable feature.
  phenotype_term:
    preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
    explanation: Confirms vestibular areflexia as a defining type-1 feature.
- category: Neurologic
  name: Delayed Motor Development
  description: >-
    Many children with type 1 do not walk before 18 months, as a consequence of
    vestibular areflexia rather than of a primary neurological deficit.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:35353227
    reference_title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Many USH1 patients do not begin to walk before the age of 18 months, and vestibular areflexia is responsible for the delayed motor development observed in these patients"
    explanation: Supports delayed walking as a vestibular consequence in type 1.
- category: Ophthalmologic
  name: Retinitis Pigmentosa
  description: >-
    Adolescent-onset progressive rod-cone dystrophy.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
    explanation: Establishes adolescent-onset retinitis pigmentosa in type 1.
- category: Ophthalmologic
  name: Constricted Visual Fields
  description: >-
    Progressive peripheral field constriction from rod loss.
  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:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
    explanation: Documents progressive visual-field constriction from rod loss.
- category: Ophthalmologic
  name: Night Blindness
  description: >-
    Nyctalopia, reflecting the rod-predominant onset of the degeneration.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:32995707
    reference_title: "Usher syndrome: clinical features, molecular genetics and advancing therapeutics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, the first presenting symptom is night blindness (nyctalopia) with progressive visual field loss beginning in the mid-periphery caused by rod photoreceptor degeneration."
    explanation: Documents nyctalopia as the first presenting retinal symptom.
- category: Ophthalmologic
  name: Abnormal Electroretinogram
  description: >-
    Electroretinography is part of the retinal functional evaluation and of
    annual 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:35353227
    reference_title: "The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As in the inner ear, USH protein defects cause diverse phenotypic abnormalities in the retina, including decreased electroretinogram responses (ERGs), probably due to misshapen photoreceptor disks"
    explanation: Model evidence supports decreased ERG responses as a readout of Usher retinal dysfunction.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of USH1 is established in a proband with characteristic findings on electrophysiologic and subjective tests of hearing and retinal function."
    explanation: >-
      Human support that retinal electrophysiology is part of establishing the
      type-1 diagnosis. It does not specify a waveform, so the direction of the
      abnormality rests on the model evidence above.
genetic:
- name: MYO7A
  association: Causative
  subtype: USH1B
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  features: >-
    Myosin VIIa, the motor element of the upper tip-link density complex.
    ClinGen's Hearing Loss Gene Curation Expert Panel classifies the
    MYO7A-Usher-syndrome-type-1 relationship as Definitive.

    MYO7A also has a separate Definitive ClinGen assertion for autosomal dominant
    nonsyndromic hearing loss (DFNA11), curated in this KB as
    Autosomal_Dominant_Nonsyndromic_Hearing_Loss_11, so a MYO7A variant has to be
    classified against a named disease entity rather than against "MYO7A disease".
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 21.0
    cohort_size: 684
    notes: >-
      144 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 1 (literature review)
    case_fraction_low: 50.0
    notes: >-
      The review states more than 50% of type 1 without an upper bound, so only the lower
      bound is recorded.
    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-1 cases attributable to MYO7A.
  evidence:
  - reference: CGGV:assertion_1e897a2f-d4cf-4e13-85d8-f37405a09b18-2018-06-28T160000.000Z
    reference_title: "MYO7A / Usher syndrome type 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYO7A | HGNC:7606 | Usher syndrome type 1 | MONDO:0010168 | AR | Definitive | SOP5 | Hearing Loss Gene Curation Expert Panel"
    explanation: ClinGen classifies the MYO7A-type 1 gene-disease relationship as Definitive against this entry's own MONDO term.
  - 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 MYO7A as the majority type-1 locus.
- name: USH1C
  association: Causative
  subtype: USH1C
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: USH1C
    term:
      id: hgnc:12597
      label: USH1C
  features: >-
    Harmonin, the scaffold of the upper tip-link density and the physical bridge
    to the type-2 ankle-link network.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 2.0
    cohort_size: 684
    notes: >-
      17 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:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms USH1C as an established type-1 gene.
- name: CDH23
  association: Causative
  subtype: USH1D
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CDH23
    term:
      id: hgnc:13733
      label: CDH23
  features: >-
    Cadherin-23, the upper element of the tip link.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 6.0
    cohort_size: 684
    notes: >-
      39 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:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms CDH23 as an established type-1 gene.
- name: PCDH15
  association: Causative
  subtype: USH1F
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PCDH15
    term:
      id: hgnc:14674
      label: PCDH15
  features: >-
    Protocadherin-15, the lower element of the tip link.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 3.0
    cohort_size: 684
    notes: >-
      21 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:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms PCDH15 as an established type-1 gene.
- name: USH1G
  association: Causative
  subtype: USH1G
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: USH1G
    term:
      id: hgnc:16356
      label: USH1G
  features: >-
    SANS, the third member of the tripartite UTLD core.
  case_fractions:
  - population: >-
      Usher syndrome of all types: 684 patients pooled from 11 next-generation sequencing
      studies
    case_fraction_percent: 1.0
    cohort_size: 684
    notes: >-
      9 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:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Confirms USH1G as an established type-1 gene.
- name: CIB2
  association: Not causative
  relationship_type: DISPUTED
  gene_term:
    preferred_term: CIB2
    term:
      id: hgnc:24579
      label: CIB2
  features: >-
    CIB2 was previously proposed as a type-1 gene (USH1J). ClinGen's Hearing Loss
    Gene Curation Expert Panel Refuted the relationship in 2019. Recorded here
    because a refuted gene-disease relationship is a curation result worth
    keeping: it stops CIB2 being re-added to a type-1 panel or to this entry.
  evidence:
  - reference: CGGV:assertion_95709038-78a4-4043-a054-9cbe245d2588-2019-02-19T170000.000Z
    reference_title: "CIB2 / Usher syndrome type 1 (Refuted)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "CIB2 | HGNC:24579 | Usher syndrome type 1 | MONDO:0010168 | AR | Refuted | SOP6 | Hearing Loss Gene Curation Expert Panel"
    explanation: ClinGen refutes CIB2 as a cause of Usher syndrome type 1.
diagnosis:
- name: Audiologic, vestibular and retinal functional evaluation
  description: >-
    Establish the clinical phenotype with subjective and electrophysiologic
    hearing and retinal testing. Vestibular testing carries particular weight here
    because areflexia is present from infancy, long before the retinal phenotype.
  results: >-
    Congenital profound hearing loss with absent vestibular responses distinguishes
    type 1 from type 2 and type 3 before retinitis pigmentosa is detectable.
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of USH1 is established in a proband with characteristic findings on electrophysiologic and subjective tests of hearing and retinal function."
    explanation: Establishes combined hearing and retinal functional testing as the clinical diagnostic route.
- name: Molecular genetic confirmation
  description: >-
    Identify biallelic pathogenic variants in one of the five type-1 genes.
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in one of five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: Establishes molecular confirmation for the five type-1 genes.
treatments:
- name: Cochlear Implantation
  description: >-
    Cochlear implantation should be considered as young as medically feasible,
    typically before age one year. The profound congenital loss of type 1 makes
    this the primary auditory intervention, in contrast to type 2 where hearing
    aids are the usual first step.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_phenotypes:
  - preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cochlear implantation should be considered as young as medically feasible, typically before age one year."
    explanation: GeneReviews recommends early cochlear implantation for the profound hearing loss of type 1.
- name: Vestibular Physical Therapy
  description: >-
    Physical therapy and vestibular rehabilitation for the areflexia and imbalance
    of type 1, beginning in childhood and continuing throughout the disease course.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy is recommended to manage vestibular dysfunction \nand imbalance throughout the disease course"
    explanation: GeneReviews recommends physical therapy for the vestibular dysfunction of type 1.
- name: Speech and Multimodal Communication Support
  description: >-
    Pair hearing technology with timely audioverbal therapy where auditory
    communication is pursued, and offer sign language from infancy so a robust
    communication modality exists before and alongside devices.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Timely audioverbal therapy following cochlear implantation is required for the development of speech."
    explanation: Supports timely audioverbal therapy after implantation.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sign language is recommended as early as birth to stimulate communication and language development prior to hearing aids and/or cochlear implants and is used throughout life as an additional means of communication when cochlear implants are not working or accessible, or as a primary means of communication for those using a nonauditory modality."
    explanation: Supports early and lifelong access to sign language rather than device-only communication.
- name: Low-Vision Rehabilitation and Psychosocial Support
  description: >-
    Orientation and adaptive-skills training as vision declines, with school or
    vocational rehabilitation and recurring mental-health support for affected
    people and families.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skills for adjusting to progressive vision loss can be accessed through school, vocational rehabilitation, or training programs."
    explanation: Supports adaptive and vocational rehabilitation for progressive vision loss.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Counseling for individuals living with USH1 and family members is recommended to manage mental health throughout the disease course, beginning in childhood and again as vision loss progresses."
    explanation: Supports longitudinal mental-health counseling for affected people and families.
- name: Audiologic and Ophthalmologic Surveillance
  description: >-
    Annual audiologic surveillance for device users and annual multimodal retinal
    surveillance beginning before visual symptoms.
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual audiometry and tympanometry in those with cochlear implants or hearing aids to assure adequate auditory stimulation."
    explanation: Supports annual audiologic surveillance for device users.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual ophthalmologic evaluation with fundus photography, visual acuity, visual field testing, electroretinography, optical coherence tomography, and fundus autofluorescence prior to the onset of visual manifestations."
    explanation: Supports annual multimodal ophthalmologic surveillance before visual manifestations.
- name: Smoking Avoidance and Sunlight Protection
  description: >-
    Counsel against tobacco smoking and recommend sunglasses and a cap to limit
    bright-light exposure as modifiable precautions for retinitis pigmentosa.
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure to bright sunlight and smoking tobacco can accelerate progression of RP. Refrain from smoking and avoid exposing eyes to sunlight by wearing sunglasses and a cap."
    explanation: Supports smoking avoidance and sunlight protection as precautions intended to limit RP progression.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal recessive recurrence risk and
    informs reproductive decision-making.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33193648
    reference_title: "Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance."
    explanation: Supports counseling for the autosomal recessive recurrence risk.
- name: Dual-AAV MYO7A Retinal Gene Therapy
  description: >-
    Investigational subretinal dual-AAV8 MYO7A gene replacement (AAVB-081) for
    USH1B retinitis pigmentosa. The dual-vector design exists because the MYO7A
    coding sequence exceeds the packaging capacity of a single AAV, which is what
    makes the choice of which MYO7A isoform to deliver a design decision with
    consequences rather than a detail.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_phenotypes:
  - preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: clinicaltrials:NCT06591793
    reference_title: A Phase 1/2 Multicenter, Open-label, Dose Escalation, Safety and Efficacy Study of Subretinal Administration of Dual AAV8.MYO7A, AAVB-081 in Subjects With Usher Syndrome Type IB (USH1B) Retinitis Pigmentosa
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of the 081-101 study is to evaluate the safety and tolerability of a single subretinal injection of AAVB-081 in USH1B patients with retinitis pigmentosa due to a mutation in the MYO7A gene."
    explanation: Establishes intervention, route, subtype scope, and MYO7A molecular eligibility.
clinical_trials:
- name: NCT06591793
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Open-label Phase 1/2 dose-escalation study of a single subretinal injection of
    dual-AAV8 MYO7A gene therapy (AAVB-081) in people with USH1B retinitis
    pigmentosa. The schema records this combined Phase 1/2 study as PHASE_I.
    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:NCT06591793
    reference_title: A Phase 1/2 Multicenter, Open-label, Dose Escalation, Safety and Efficacy Study of Subretinal Administration of Dual AAV8.MYO7A, AAVB-081 in Subjects With Usher Syndrome Type IB (USH1B) Retinitis Pigmentosa
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of the 081-101 study is to evaluate the safety and tolerability of a single subretinal injection of AAVB-081 in USH1B patients with retinitis pigmentosa due to a mutation in the MYO7A gene."
    explanation: Registry record establishing the USH1B gene-therapy trial.
discussions:
- discussion_id: ush1_mouse_lacks_calyceal_processes
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can a mouse model report on the type-1 retinal mechanism at all, given that
    mice have no calyceal processes?
  attaches_to:
  - pathophysiology#Photoreceptor Calyceal Process Network Disruption
  rationale: >-
    The classical type-1 mouse models are deaf without retinal degeneration, and
    the usual explanation has been species differences in where individual
    proteins are expressed. A structural explanation covers all five genes at
    once: the mouse photoreceptor lacks calyceal processes entirely, so the
    structure the type-1 protein network builds in human, macaque and frog does
    not exist in the model organism. That makes the absent retinal phenotype an
    expected consequence of the model rather than evidence against the mechanism,
    and it means a negative retinal result in mouse carries very little weight
    for this entity.

    This bears directly on preclinical efficacy testing for MYO7A gene therapy: a
    mouse retina cannot report restoration of a structure it never had.
  evidence:
  - reference: PMID:23045546
    reference_title: "Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface."
    explanation: States the structural absence that makes the mouse retina uninformative for this mechanism.
notes: >
  MONDO coverage of the type-1 subtype series, and the type-1 concepts deliberately not
  curated here. Each of the five locus subtypes now binds its own MONDO term - USH1B
  MONDO:0700087, USH1C MONDO:0010171, USH1D MONDO:0010984, USH1F MONDO:0011186, USH1G
  MONDO:0011748 - and a sixth row, USH1DF, binds MONDO:0100050 for the digenic
  CDH23-plus-PCDH15 form, whose inheritance claim neither the USH1D nor the USH1F row
  describes. MONDO's parentage agrees: all six are children of MONDO:0010168, this entry's
  own term.

  MONDO:0010984 carries no causal-gene axiom in the release read on 2026-09-24, even though
  CDH23 is one of the five established type-1 genes, so a gene-keyed knowledge-graph
  comparison cannot see it. That is an upstream gap rather than a gap here.

  Three further children of MONDO:0010168 are declined as locus-only concepts: Usher
  syndrome type 1E (MONDO:0011195), type 1H (MONDO:0012968) and type 1K (MONDO:0014001).
  MONDO's definitions give a chromosome band and no gene for each, and none carries a
  causal-gene axiom, so there is nothing for a subtype row to bind that this entry does not
  already assert.

  Two Usher-named MONDO concepts belong to type 1 and are declined for stated reasons. Usher
  syndrome type 1J has been retired: MONDO:0013935 is marked owl:deprecated with
  term-replaced-by MONDO:0012273, autosomal recessive nonsyndromic hearing loss 48, which
  carries USH1J and Usher syndrome type 1J as exact synonyms, is axiomatized on CIB2, and
  sits under hearing loss rather than under Usher syndrome. dismech curates that disease as
  Autosomal_Recessive_Nonsyndromic_Hearing_Loss_48, which is consistent with the DISPUTED
  CIB2 record below. Usher syndrome, type 1M (MONDO:0032841) is still live but is a direct
  subclass of MONDO:0003847 hereditary disease rather than of Usher syndrome, has no text
  definition and no causal-gene axiom, and the ESPN assignment reported for USH1M is marked
  with a question mark in the ultra-rare-gene table of PMID:35353227; it is declined pending
  an upstream MONDO fix and better gene evidence.

  Reading the case fractions below: the meta-analysis denominator is all Usher syndrome,
  not type 1. Only the MYO7A record carries a type-specific figure, because that is the only
  gene for which a type-1 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 upper tip-link density complex, not by the clinical
  type. The numbered label is retained because ClinGen and MONDO both curate at
  that identity - ClinGen's Hearing Loss Gene Curation Expert Panel asserts all
  five type-1 genes against MONDO:0010168, the same term this entry binds - but
  the clinical typing is an imperfect proxy for the mechanism, and the entry
  description says so.

  Two nodes replace what the lumped entry carried as one. The retained
  "Photoreceptor Connecting Cilium Dysfunction" node was wrong for this entity:
  the type-1 retinal structure is the calyceal-process adhesion belt, a different
  subcellular compartment from the type-2 periciliary membrane complex. The
  hair-bundle node is scoped to the mature tension-bearing UTLD rather than to the
  transient ankle-link complex that carries the type-2 mechanism.

  Subtypes are named for the locus (USH1B, USH1D, USH1F) rather than the gene,
  because USH1C and USH1G are simultaneously locus designations and HGNC gene
  symbols and a gene-symbol convention would be ambiguous for two of the five.

  Not curated here, deliberately: no per-entity prevalence is asserted, because
  the source the lumped entry cited (4-17 per 100,000) reports that figure for
  Usher syndrome as a whole and splitting it across four entities would invent
  four numbers no source states; the `Grouping` class has no prevalence slot
  either, so the combined figure is carried in the grouping's prose. The five
  nonsyndromic DFNB stubs for these genes are left to issue #9863 rather than
  absorbed, and the isoform-selection question for
  MYO7A gene therapy is named in the treatment description but is not curated as a
  mechanistic_hypotheses group, because no evidence in this entry's reference set
  bears on which isoform a vector should carry.
📚

References & Deep Research

References

17
PMID:20301442
Usher Syndrome Type I.
No top-level findings curated for this source.
PMID:21709241
Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.
No top-level findings curated for this source.
PMID:23045546
Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice.
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: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:35353227
The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification.
No top-level findings curated for this source.
No top-level findings curated for this source.
No top-level findings curated for this source.
clinicaltrials:NCT06591793
A Phase 1/2 Multicenter, Open-label, Dose Escalation, Safety and Efficacy Study of Subretinal Administration of Dual AAV8.MYO7A, AAVB-081 in Subjects With Usher Syndrome Type IB (USH1B) Retinitis Pigmentosa
No top-level findings curated for this source.
PMID:15537665
Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans.
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:7870171
Defective myosin VIIA gene responsible for Usher syndrome type 1B.
No top-level findings curated for this source.
PMID:10973247
A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C.
No top-level findings curated for this source.
PMID:11138009
Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D.
No top-level findings curated for this source.
PMID:11398101
Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.
No top-level findings curated for this source.
PMID:12588794
Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin.
No top-level findings curated for this source.