Clinical Guidance

A genotype-phenotype correlation has been reported for pathogenic variants in the genes associated with USH1. Homozygous null (e.g., nonsense, frameshift, splicing) variants are associated with USH1, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic hearing impairment or atypical Usher syndrome. This genotype-phenotype correlation suggests that deaf children found to be homozygous for hypomorphic variants in an USH1 gene are unlikely to develop vision loss.

USH1C

Source: GeneReviews — "Usher Syndrome Type I"

Penetrance

Penetrance is complete in Usher syndrome type I.

Source: GeneReviews — "Usher Syndrome Type I"

Diagnostic Criteria

Suggestive Findings

Usher syndrome type I (USH1) should be suspected in individuals with:

• Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see Hereditary Hearing Loss and Deafness Overview);

• No significant or delayed vestibular responses;

• Retinitis pigmentosa (RP);

• Normal general health and intellect and otherwise normal physical examination;

• A family history consistent with autosomal recessive inheritance.

Establishing the Diagnosis

The diagnosis of USH1 is established in a proband with the above . Identification of biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in establishes the diagnosis if clinical features are inconclusive.

Source: GeneReviews — "Usher Syndrome Type I"

Differential Diagnosis

Nonsyndromic hearing loss (NSHL). Often, a family with more than one affected sib is thought to have NSHL (see Hereditary Hearing Loss and Deafness Overview) until the oldest affected sib manifests signs of retinal degeneration (e.g., night blindness, dark adaptation impairment, contrast vision difficulties, visual acuity changes, and visual field narrowing) and is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic signs of RP in younger affected sibs. While the timing and extent of vestibulopathy related to Usher syndrome is not fully defined, vestibular symptoms in young children thought to have NSHL may also prompt visual evaluation and subsequent genetic testing. Coinheritance of NSHL and RP. Pathogenic variants associated with separate NSHL and RP (e.g., OTOA-NSHL and NR2E3-RP ) can be inherited independently by a single individual whose symptoms can then mimic those of Usher syndrome . Larger families lessen the statistical probability of this occurrence because at least one sib is likely to inherit one pathogenic variant without the other. NSHL and RP (or inherited retinal degeneration) are both relatively common, with frequencies of 1:1,000 and 1:3,000, respectively, and are both characterized by extreme genetic heterogeneity (to date, 110 genes have been associated with NSHL, 60 genes have been associated with RP, and 172 genes have been associated with inherited retinal degeneration) . See also Hereditary Hearing Loss and Deafness Overview and RetNet: Retinal Information Network. Hereditary disorders characterized by both sensorineural hearing impairment (SNHI) and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type I (USH1) are summarized in . Table 3. Genes of Interest in the Differential Diagnosis of Usher Syndrome Type I

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type I (USH1), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type I

System/Concern | Evaluation | Comment

Audiology

| Otoscopy, pure tone audiometry, assessment of speech perception | Consider ABR, ECOG, DPOAE.

Vestibular

function | Rotary chair, VNG incl calorics, computerized posturography | Consider VHIT, vestibular evoked myogenic potentials (cVEMP oVEMP).

Ophthalmology

| Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, dark-adapted rod perimetry), ERG, OCT, FAF | • Fundus photography documents the extent of pigmentation retinal/RPE atrophy.

• VA is often maintained until late in the disease.

• VF maps the extent of functional peripheral vision, retinal sensitivities, functional rod cone responses.

• ERG is often nondetectable at presentation.

• OCT allows the determination of "live" photoreceptors (measuring the ellipsoid zone).

• FAF can measure the perifoveal hyperfluorescent ring, lipofuscin disturbance.

Other

| Consultation w/clinical geneticist /or genetic counselor |

Source: GeneReviews — "Usher Syndrome Type I"

Clinical Guidance

Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous. Persons with USH1 often become disoriented when submerged in water because they lack the sense of where "up" is; they should therefore exercise caution while swimming. Similarly, the vestibular dysfunction increases the risk of falls when walking on sloped or uneven surfaces. Progressive loss of peripheral vision may eventually impair the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.

Source: GeneReviews — "Usher Syndrome Type I"

Therapies Under Investigation

UshStat®

gene replacement of MYO7A – A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of UshStat® in Patients with Usher Syndrome Type 1B. This is an interventional, Phase I/II clinical trial to evaluate the safety and activity of retinal gene therapy to treat RP in individuals with MYO7A-USH1. This trial is active but not recruiting. (See NCT02065011.) QR-421 antisense treatment – A Study to Evaluate Safety and Tolerability of QR-421a in Subjects with RP Due to Mutations in Exon 13 of the USH2A Gene (Stellar). This is an interventional, Phase I/II clinical trial to evaluate the safety of an antisense oligonucleotide (ASO) therapy to treat RP in individuals with USH2 due to specific USH2A pathogenic variants. (See NCT03780257.

Source: GeneReviews — "Usher Syndrome Type I"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with Usher Syndrome Type I

System/Concern | Evaluation | Frequency

Hearing loss

| Audiometry tympanometry w/cochlear implant or hearing aids to assure adequate auditory stimulation | • For persons w/o profound loss, annual testing allows appropriate hearing aid adjustment.

• For cochlear implant recipients, annual follow up is necessary to assure appropriate implant function programming.

• Children w/profound loss cochlear implants can still develop fluid chronic ear infection issues, which are less evident to the child because of hearing loss. Annual otoscopic exam w/tympanometry avoids potential serious complications of chronic otitis media.

Cataracts

| Ophthalmologic eval | Annually from age 20 yrs or from age at diagnosis

Cystoid

macular edema

Retinitis

pigmentosa | Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, dark-adapted rod perimetry), ERG, OCT, FAF

ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field

Source: GeneReviews — "Usher Syndrome Type I"