Clinical characteristics.

Usher syndrome type II (USH2) is characterized by the following:

• Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies
• Intact or variable vestibular responses
• Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families.

Diagnosis/testing.

The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Early fitting of hearing aids and speech training. Children with incomplete speech and sentence rehabilitation with hearing aids and older individuals with severe-to-profound hearing loss should be considered for cochlear implantation. Standard treatments for retinitis pigmentosa; vestibular rehabilitation.

Surveillance: Annual audiometry and tympanometry with hearing aids or cochlear implant to assure adequate auditory stimulation. Annual ophthalmologic evaluation from age 20 years to detect potentially treatable complications such as cataracts, refractive errors, and cystoid macular edema. Annual fundus photography, visual acuity, visual field, electroretinography, optical coherence tomography, and fundus autofluorescence from age ten years.

Agents/circumstances to avoid: Tunnel vision and night blindness can increase the likelihood of accidental injury. Competition in 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.

Evaluation of relatives at risk: The hearing of at-risk sibs should be assessed as soon after birth as possible to allow early diagnosis and treatment of hearing loss.

Genetic counseling.

USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child, a 50% chance of resulting in an unaffected child who is a carrier, and a 25% chance of resulting in an unaffected child who is not a carrier. Prenatal testing and preimplantation genetic testing are possible for pregnancies at increased risk if the pathogenic variants have been identified in the family.

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 above clinical features and family history. Identification of biallelic pathogenic variants in one of the genes listed in Table 1 establishes the diagnosis if clinical features are inconclusive.

The phenotype of USH2 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP, therefore the recommended molecular testing approaches can include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing is rarely useful and typically NOT recommended.

• An Usher syndrome multigene panel or a more comprehensive multigene panel (e.g., inherited retinal dystrophy panel, hereditary hearing loss panel) that includes the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Usher syndrome type II (USH2) is characterized by moderate-to-severe sensorineural hearing loss at birth and retinitis pigmentosa (RP) that begins in late adolescence or early adulthood. Some individuals also have vestibular loss [Yang et al 2012, Blanco-Kelly et al 2015, Magliulo et al 2017].

Phenotype Correlations by Gene

Sadeghi et al [2004] compared serial audiograms of individuals with USH2 who had pathogenic variants in USH2A (group 1) with those of individuals diagnosed with USH2 who did not have pathogenic variants in USH2A (group 2). They found significantly worse thresholds in group 1 than in group 2 after the second decade. These results suggested that the USH2A-USH2 auditory phenotype may be different from that of other subtypes of USH2. Abadie et al [2012], however, did not find any significant differences between the audiograms from 88 individuals with pathogenic variants in USH2A and ten individuals with pathogenic variants in ADGRV1.

Schwartz et al [2005] did not observe any genotype-phenotype correlations between individuals with pathogenic variants in USH2A and those with variants in ADGRV1; however, only three sibs with pathogenic variants in ADGRV1 were evaluated. They found a wide spectrum of photoreceptor disease with more rod than cone dysfunction, and both intra- and interfamilial variation for USH2A-USH2.

Frenzel et al [2012] performed two measures of touch sensation (tactile sensation and vibrational detection threshold) on two cohorts of individuals with USH2 from Germany and Spain. USH2A variants were associated with poor touch acuity as well as congenital hearing loss and adult-onset RP.

Genotype-Phenotype Correlations

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 [Lenassi et al 2015b, Hartel et al 2016, Jung 2020]. The visual phenotype in individuals with USH2A-USH2 pathogenic variants is associated with more severe RP compared with nonsyndromic USH2A-RP [Pierrache et al 2016, Sengillo et al 2017, Gao et al 2020]. The hearing phenotype in individuals with USH2A-USH2 is more severe and progressive in individuals with one or more deleterious USH2A variants [Hartel et al 2016, Jung 2020].

Lenassi et al [2015b] 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. A correlation between severity of hearing loss and severity of RP was not found.

Individuals of Swedish or Dutch origin with biallelic USH2A truncating variants (including homozygous c.2299delG variants) developed significantly more severe and progressive hearing loss than individuals with one truncating USH2A variant combined with one nontruncating variant and individuals with two nontruncating variants. Similar findings were also reported in individuals of Korean ancestry [Hartel et al 2016, Jung 2020].

Penetrance

Penetrance is 100% in USH2.

Nomenclature

The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, the presence or absence of vestibular areflexia, and the age of onset of retinitis pigmentosa). The letter following USH2 indicates the molecular subtype caused by biallelic variants in one of the related genes listed in Table 1.

Prevalence

The prevalence of Usher syndrome in the general US population has been conservatively estimated at 4.4:100,000. However, a study of children with hearing loss in Oregon found that 11% had pathogenic variants in genes associated with Usher syndrome and estimated that the prevalence may be as high as 1:6,000 [Kimberling et al 2010].

Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. These estimates were made prior to 1989, when Möller et al [1989] subdivided Usher syndrome into USH1 and USH2, and USH3 had not yet been recognized. The specialized educational requirements of the congenitally deaf have historically rendered the population with USH1 more accessible for study by researchers. Persons with USH2 or USH3 communicate orally and are mainstreamed into regular schools; thus, the prevalence of USH2 and USH3 in the general population cannot be estimated as accurately as that of USH1. Often, persons with USH2 are not diagnosed until early adulthood, when progressive RP becomes debilitating.

The prevalence of Usher syndrome in Heidelberg, Germany and its suburbs has been calculated to be 6.2:100,000 [Spandau & Rohrschneider 2002]. In that study, the ratio of USH1 to USH2 was 1:3.

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 in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

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.

Evaluation of Relatives at Risk

It is appropriate to evaluate all sibs at risk for USH2 as soon after birth as possible to allow early support and management of the child and the family. Evaluations include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Pregnancy Management

High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (doses above the RDA for pregnant or lactating women) may be teratogenic to the developing fetus (see Other).

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).

CL-17-01 antioxidant treatment. Phase I, Single- and Multiple-Ascending Dose Study of the Safety and Tolerability of NPI-001 Solution in Healthy Subjects. This clinical trial established that NPI-001 was generally well tolerated in all but the highest dose and determined key pharmacokinetic parameters of the NPI-001 solution (search on ACTRN12617000911392 at www.anzctr.org.au).

Search ClinicalTrials.gov in the US, EU Clinical Trials Register in Europe, and ANZCTR Trial Search in Australia and New Zealand for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamin A supplements. Vitamin A plays an essential role in the visual (retinoid) cycle as the photosensitive intermediate 11 cis retinal. Although treatment with vitamin A palmitate may limit the progression of RP in persons with isolated RP and USH2, no studies have evaluated the effectiveness of vitamin A palmitate in individuals with USH2. Vitamin A is fat soluble and not excreted in the urine. Therefore, high-dose vitamin A dietary supplements should be used only under the direction of a physician because of the need to monitor for harmful side effects such as hepatotoxicity [Sibulesky et al 1999]. Of note, the studies by Berson et al [1993] were performed on individuals older than age 18 years because of the unknown effects of high-dose vitamin A on children. High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (i.e., above the recommended daily allowance for pregnant or lactating women) may be teratogenic to the developing fetus.

Lutein supplements may enhance retinal macular pigment. Lutein, zeaxanthin, meso-zeaxanthin, and their oxidative metabolites accumulate in the human fovea and macula as the macular pigment (MP). They are obtained through dietary sources (green leafy vegetables, yellow and/or orange fruits and vegetables). Inherited retinal dystrophies may cause or be associated with loss of MP [Aleman et al 2001]. Oral administration of lutein (20 mg/d) for seven months had no effect on central vision [Aleman et al 2001]. However, Berson et al [2010] showed that lutein supplementation of 12 mg/d slowed loss of midperipheral visual field among nonsmoking adults with RP taking vitamin A.

Omega 3 supplements (e.g., docosahexaenoic acid [DHA]) may replenish membranes of the photoreceptor outer segments, which are largely composed of polyunsaturated fatty acids. Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity [Hoffman et al 2015].

N-acetyl-cysteine (NAC) supplements. NAC is a safe oral antioxidant used to treat liver toxicity due to acetaminophen overdose. NAC reduces oxidative damage and increases cone function and survival in animal models of RP [Lee et al 2011]. In a Phase l study, 600 mg, 1200 mg, or 1800 mg were safe in individuals with RP and significant improvements were found in cone function, including visual acuity [Campochiaro et al 2020].

Blueberry extract supplements. Blueberry fruits contain anthocyanins, members of the flavonoid group of phytochemicals, which are powerful antioxidants. No studies have been done on individuals with RP or USH2. Because of their natural occurrence, they are probably safe and may be efficacious.

Mode of Inheritance

Usher syndrome type II (USH2) is inherited in an autosomal recessive manner.

Digenic inheritance and/or disease-modifier genes

• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [Zheng et al 2005, Bonnet et al 2011, Vozzi et al 2011, Yoshimura et al 2014].
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving PDZD7 (see Molecular Genetics), only two studies have reported evidence of digenic inheritance: Ebermann et al [2010] described an individual with USH2 with heterozygous pathogenic variants in both ADGRV1 and PDZD7; Yoshimura et al [2014] described an individual with USH1 with heterozygous pathogenic variants in both MYO7A and PCDH15. Large meta-analysis of the genetics of Usher syndrome by Jouret et al [2019] concluded that data "do not support the existence of digenic inheritance in Usher syndrome" and suggest that the affected individuals in the above-referenced studies may have had genetic variants undetectable by the genetic testing capabilities available at the time.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• The unaffected parents of an individual with USH2 are obligate heterozygotes (i.e., presumed to be carriers of one ADGRV1, USH2A, or WHRN pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an USH2-causing pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an USH2-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Considerable variability in the degree of hearing loss and the rate and degree of vision loss may be observed among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an individual with USH2 has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH2-related gene.
• The carrier frequency of pathogenic variants in USH2A is estimated at approximately 1:70 as an average across most ethnic populations. Importantly, many pathogenic variants in USH2A are associated with retinitis pigmentosa (RP) in the absence of hearing loss ("retinal disease-specific variants"). As a result, families segregating a retinal disease-specific USH2A variant and an USH2A pathogenic variant not specific to retinal disease only may have multiple affected individuals, with some developing USH2 and others with nonsyndromic RP [Lenassi et al 2015a].
• Thus, for each pregnancy of a couple in which one partner has USH2 and the other partner has normal vision and no family history of USH2 or RP, the probability of a child having USH2 or RP due to biallelic pathogenic variants in USH2A is approximately 1:140.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in an USH2-related gene.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the USH2-causing pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA and/or cellular banking is the storage of DNA (typically extracted from white blood cells) or cells for possible future use in research to improve our understanding of Usher syndrome and to develop new therapies. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA and/or cells of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the USH2-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The proteins associated with Usher syndrome type I (USH1) and Usher syndrome type II (USH2) interact with one another in the "Usher interactome." When one of these proteins is nonfunctional or absent, sensorineural degeneration occurs in the inner ear and the retina [Bonnet & El-Amraoui 2012, Mathur & Yang 2015, Géléoc & El-Amraoui 2020]. The USH2-related proteins include the following.

ADGRV1, encoded by ADGRV1

• Member of subgroup of the large N-terminal family B seven-transmembrane receptors
• Contains pentaxin (PTX) domains, similar to USH2A; may share binding partners
• Contains cadherin domains similar to USH1 proteins CDH23 and PCDH15
• Expressed as multiple variants that comprise isoforms a, b, and c [Reiners et al 2006]

Usherin, encoded by USH2A

• Expressed as two alternatively spliced isoforms that comprise a short "isoform a" (21 exons, 1546 amino acids) and a longer "isoform b" (72 exons, 5202 amino acids)
• Isoform a is a secreted protein that contains 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), and 4 fibronectin III (FN3) domains [Weston et al 2000].
• Isoform b is a transmembrane protein. The extracellular N-terminal end contains 1 laminin globular-like (LGL), 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), 2 laminin globular (LG), and 32 firbronectin III (FN3) domains. The intracellular C-terminal end contains a PDZ-binding domain (PBD) that interacts with other USH and deafness proteins in retinal photoreceptors and inner ear hair cells [van Wijk et al 2004, van Wijk et al 2006, Michalski et al 2007, Yang et al 2010, Zou et al 2011, Yu et al 2020].
• Usherin colocalizes with and binds to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [Bhattacharya et al 2002, Pearsall et al 2002, Bhattacharya et al 2004].

Whirlin, encoded by WRHN

• Expressed as multiple transcripts with two predicted promotor regions and alternative splicing that encode full-length (FL)-, N-, and C-terminal whirlin proteins [Mathur & Yang 2019]
• FL-whirlin has two harmonin N-like (HNL), three PDZ, one proline-rich (PR), and one PDZ-binding domain (PBD) [Mathur & Yang 2019].
• Whirlin interacts in vivo with usherin and ADGRV1, suggesting that these three proteins function as a multiprotein complex in both the stereocilia of the cochlear hair cells and the periciliary membrane complex of the retinal photoreceptor cells [Yang et al 2010].

Another PDZ domain-containing protein, PDZD7, was identified as a result of a study of a child with nonsyndromic sensorineural hearing loss and a homozygous reciprocal translocation; protein-protein interaction studies indicated that PDZD7 is a part of the Usher protein network [Schneider et al 2009]. Pathogenic variants in PDZD7 have not yet been shown to cause Usher syndrome, but it has been suggested that PDZD7 pathogenic variants may act as modifiers of the retinal phenotype in individuals with USH2A-USH2.

Mechanism of disease causation. Pathogenic variants in USH2-causing genes result in defects in cochlear hair cell development and photoreceptor cell maintenance. The autosomal recessive inheritance of USH2 strongly suggests a loss-of-function mechanism.

Acknowledgments

Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital

Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha

Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden

Research supported by FFB and NIH

Author History

Moises Arriaga, MD, MBA, FACS (2020-present)
Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)
William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)
Robert Koenekoop, MD, PhD, FARVO (2020-present)
Jennifer Lentz, PhD (2006-present)
Dana J Orten, PhD; Boys Town National Research Hospital (2003-2006)
Sandra Pieke-Dahl, PhD; Ohio State University (1999-2003)
Karmen M Trzupek, MS, CGC (2020-present)
Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)

Revision History

• 22 October 2020 (sw) Comprehensive update posted live
• 21 July 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 29 December 2011 (cd) Revision: deletion/duplication analysis available for GPR98 and DFNB31
• 23 December 2010 (me) Comprehensive update posted live
• 14 April 2009 (me) Comprehensive update posted live
• 5 November 2007 (cd) Revision: prenatal diagnosis for Usher syndrome type 2A available
• 14 November 2006 (me) Comprehensive update posted live
• 20 October 2004 (wk) Revision: sequencing of entire coding region available
• 13 January 2004 (wk) Revision: change in test availability
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission

Published Guidelines / Consensus Statements

• American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available online. 2002. Accessed 10-14-20.
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 10-14-20.

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