Clinical Guidance

USH2A. Deleterious null (e.g., nonsense, frameshift, splicing) variants are associated with USH2, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic RP . The visual phenotype in individuals with USH2A-USH2 pathogenic variants is associated with more severe RP compared with nonsyndromic USH2A-RP . The hearing phenotype in individuals with USH2A-USH2 is more severe and progressive in individuals with one or more deleterious USH2A variants . designated retinal disease-specific pathogenic variants in USH2A that cause RP with preservation of normal hearing. While these individuals did not report hearing loss, audiometric testing found variable hearing loss in a substantial number.

Source: GeneReviews — "Usher Syndrome Type II"

Penetrance

Penetrance is 100% in USH2.

Source: GeneReviews — "Usher Syndrome Type II"

Diagnostic Criteria

Suggestive Findings

Usher syndrome type II (USH2) should be suspected in individuals with:

• Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see Hereditary Hearing Loss and Deafness Overview);

• Intact or variable vestibular responses;

• Retinitis pigmentosa (RP);

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

• A family history consistent with autosomal recessive inheritance.

Establishing the Diagnosis

The diagnosis of USH2 is established in a proband with the clinical features and family history. 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 II"

Differential Diagnosis

Often, a family with more than one affected sib is thought to have nonsyndromic hearing loss (NSHL) (see Hereditary Hearing Loss and Deafness Overview) until the oldest is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic early stages of RP in younger affected sibs. Pathogenic variants associated with NSHL and RP can be inherited independently by a single individual whose symptoms 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 are both relatively common, with frequencies of 1:1,000 and 1:4,000, respectively, and are characterized by extreme genetic heterogeneity (to date, 110 genes have been associated with NSHL and 80 genes have been associated with RP). Hereditary disorders characterized by both sensorineural hearing impairment and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type II (USH2) are summarized in . Table 4. Genes of Interest in the Differential Diagnosis of Usher Syndrome Type II

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type II (USH2), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type II

Source: GeneReviews — "Usher Syndrome Type II"

Clinical Guidance

Competition in various sports requiring a full range of vision may be difficult and possibly dangerous. Progressive loss of peripheral vision impairs 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 II"

Therapies Under Investigation

QR-421 antisense treatment. 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. This study is active and recruiting (see ClinicalTrials.gov). C-18-04 antioxidant treatment. Safety and Efficacy of NPI-001 Tablets for Retinitis Pigmentosa Associated with Usher Syndrome (SLO RP). This is an interventional, two-year, Phase I/II clinical trial to evaluate the safety and efficacy of NPI-001 tablets in individuals with RP associated with Usher syndrome. This trial is active and recruiting (see ClinicalTrials.gov).

Source: GeneReviews — "Usher Syndrome Type II"

Surveillance Guidelines

Table 7. Recommended Surveillance for Individuals with Usher Syndrome Type II

Source: GeneReviews — "Usher Syndrome Type II"