Summary
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.
Diagnosis
Suggestive Findings
Usher syndrome type II (USH2) should be suspected in individuals with:
Establishing the Diagnosis
The diagnosis of USH2 is established in a proband with the above clinical features and family history. Identification of biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1 establishes the diagnosis if clinical features are inconclusive.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in one of the genes listed in Table 1 does not establish or rule out the diagnosis.
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 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.
Table 1.
Molecular Genetic Testing Used in Usher Syndrome Type II (USH2)
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Gene 1, 2 | USH2 Subtype | Proportion of USH2 Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detected by Method |
---|
Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 |
---|
ADGRV1
| USH2C | 6.6%-19% 6 | >90% 7 | 3/49 individuals 8 |
USH2A
| USH2A | 57%-79% 6 | >90% 7, 9 | 6%-9% 10, 11 |
WHRN
| USH2D | 0%-9.5% 6 | >95% 7 | None reported 7 |
Unknown 12, 13 | | | NA |
- 1.
Genes are listed in alphabetic order.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
- 7.
- 8.
- 9.
- 10.
- 11.
- 12.
- 13.
To date, PDZD7 pathogenic variants have not been shown to cause Usher syndrome but may act as modifiers of the retinal phenotype in individuals with USH2A-related USH2 [Ebermann et al 2010]. Additionally, an individual with USH2 and compound heterozygous pathogenic variants in USH2A and PDZD7 and another affected individual with compound heterozygous variants in ADGRV1 and PDZD7 were reported, leading to the suggestion of digenic inheritance [Ebermann et al 2010].
Clinical Characteristics
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].
Table 2.
Select Features of Usher Syndrome Type II
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Feature | % of Persons w/Feature | Comment |
---|
Hearing loss | 100% | High-frequency loss which is usually stable |
RP | 100% | Variable age of onset & rate of progression |
Vestibular loss | 40%-80% | Usually asymptomatic but identifiable on specialized testing 1 |
RP = retinitis pigmentosa
- 1.
Hearing Loss
The hearing loss in USH2 is typically congenital and bilateral, occurring predominantly in the higher frequencies and ranging from moderate to severe. The degree of hearing loss varies within and among families; however, the "sloping" audiogram is characteristic of USH2. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases, possibly as a result of diminished vision that interferes with subconscious lip reading. Hearing aids are usually adequate in individuals with USH2. Cochlear implants are highly effective if speech and sentence testing indicates inadequate response with hearing aids.
Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with USH2A-USH2 confirmed by linkage analysis compared hearing threshold against age; significant progression of hearing impairment was observed but at a much slower rate than reported for Usher syndrome type III (USH3) [Pennings et al 2003]. In contrast, in a large study of 125 individuals with USH2, Reisser et al [2002] found no clinically relevant progression of hearing loss over a span of up to 17 years.
Visual Loss
Children with USH2 are often misdiagnosed as having nonsyndromic hearing impairment until tunnel vision and night blindness (early signs of RP) become severe enough to be noticeable, either by parents and teachers or by the individual. The onset of RP in individuals with USH2 is variable but typically starts in late adolescence or early adulthood and occasionally can start much earlier. RP is progressive, bilateral, symmetric photoreceptor degeneration of the retina that initiates in the mid-periphery; rods (photoreceptors active in the dark-adapted state) are mainly affected first, causing night blindness and constricted visual fields (tunnel vision). Cones (photoreceptors active in the light-adapted state) are affected second and eventually die and cause central blindness. Contrast sensitivities, color vision, and mobility may become severely affected as the retinal degeneration progresses.
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH2 at age 30-40 years. Visual impairment worsens significantly each year [Iannaccone et al 2004, Pennings et al 2004]. Individuals with USH2 may become completely blind. Cataracts and/or cystoid macular edema sometimes reduce central vision. These two associated conditions are treatable.
Vestibular Loss
Vestibular loss has been identified in 40%-80% of individuals with USH2 in a small study of specialized vestibular testing [Magliulo et al 2017]. However, these individuals were found to be asymptomatic suggesting that they compensate for the loss of vestibular function.
Heterozygotes
Heterozygotes are asymptomatic; however, they may exhibit audiogram anomalies that are not sensitive or specific enough for carrier detection.
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 2021]. 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.
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 [Fakin et al 2012]. 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.
Table 4.
Genes of Interest in the Differential Diagnosis of Usher Syndrome Type II
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Gene(s) | Disorder | MOI | Clinical Characteristics | Comment |
---|
CDH23
CIB2
MYO7A
PCDH15
USH1C
USH1G
|
USH1
| AR | Congenital bilateral profound SNHL, vestibular areflexia, adolescent-onset RP | Children w/USH1 are usually do not walk until age 18 mos to 2 yrs due to vestibular involvement (those w/USH2 usually walk at age ~1 yr). |
CLRN1
HARS1
| USH3 (OMIM 276902, 614504) | AR | Postlingual progressive SNHL, late-onset RP, variable impairment of vestibular function | Some persons w/USH3 may have profound HL & vestibular disturbance & thus be clinically misdiagnosed w/USH1 or USH2. 1 |
PEX1 PEX6 PEX12 (13 genes) 2 | Zellweger spectrum disorder (ZSD) 3 | Intermediate/ milder ZSD | AR (AD) 4 | Mainly sensory deficits &/or mild developmental delay; intellect may be normal. | Milder ZSD & USH2 can both have SNHL & retinal pigmentary abnormalities, but visual impairment in milder ZSD is more variable. Also, those w/milder ZSD typically develop ameliogenesis imperfecta of secondary teeth. |
Severe ZSD | AR | Severe neurologic dysfunction, craniofacial abnormalities, liver disfunction, absent peroxisomes | Infants w/severe ZSD are significantly impaired & usually die during 1st yr of life, usually having made no developmental progress. |
PEX7
PHYH
|
Refsum disease
| AR | RP, HL, anosmia, polyneuropathy, ataxia | RP is nearly always 1st noticeable feature; anosmia, polyneuropathy, & then mild-to-moderate HL follow. |
ABHD12
| Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, & cataract (PHARC) (OMIM 612674) | AR | Polyneuropathy, HL, ataxia, RP, cataract | Persons w/PHARC typically develop polyneuropathy & ataxia in teens or early adulthood; & RP typically later in adulthood. |
TIMM8A 5 | Deafness-dystonia-optic neuronopathy syndrome (DDON) | XL | Males: pre- or postlingual SNHL in early childhood; optic atrophy → slowly progressive ↓ visual acuity from age ~20 yrs; dementia from age ~40 yrs; slowly progressive dystonia or ataxia in the teens 6 Females: mild hearing impairment & focal dystonia | In DDON, appearance of the retina, night vision, & ERG are usually normal; in USH, impaired vision results from retinal dystrophy that first manifests as impaired dark adaptation. 7 |
- 1.
- 2.
60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in PEX1, 14.5% with pathogenic variants in PEX6, and 7.6% with pathogenic variants in PEX12. In total, 13 genes are known to be associated with ZSD.
- 3.
The term "Zellweger spectrum disorder" refers to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.
- 4.
One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.
- 5.
- 6.
In DDON syndrome, hearing impairment appears to be constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs (e.g., personality change and paranoia) vary in degree of severity and rate of progression.
- 7.
Other. Viral infections, diabetic neuropathy, and syndromes involving mitochondrial defects (see Mitochondrial Disorders Overview) can all produce concurrent symptoms of hearing loss and retinal pigmentary changes that suggest Usher syndrome.
Management
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.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type II
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System/Concern | Evaluation | Comment |
---|
Audiology
| Otoscopy, puretone audiometry, assessment of speech perception | Consider auditory brain stem response (ABR), electrocochleography (ECOG), and distortion product otoacoustic emission (DPOAE). Speech and sentence tests with hearing aids will determine if cochlear implantation offers better rehabilitation than hearing aids. |
Vestibular
function
| Rotary chair, calorics, electronystagmography, ocular & cervical myogenic evoked potentials, video head impulse testing, computerized posturography | Persons describing imbalance or dizziness should undergo comprehensive vestibular testing to guide rehabilitation. |
Ophthalmology
| Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, Dark adapted rod perimetry), ERG, OCT, FAF | Fundus photography documents extent of pigmentation & RPE atrophy; VA is often maintained until late in disease; VF maps extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses. ERG is often nondetectable at presentation; OCT allows determination of "live" photoreceptors (measuring the ellipsoid zone); FAF can measure the perifoveal hyperfluorescent ring lipofuscin disturbance. |
Genetic
counseling
| By genetics professionals 1 |
To inform affected individuals & families re nature, MOI, & implications of USH2 in order to facilitate medical & personal decision making
|
Family support
& resources
| Assess need for:
| |
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Table 6.
Treatment of Manifestations in Individuals with Usher Syndrome Type II
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Manifestation/ Concern | Treatment | Considerations/Other |
---|
Hearing loss
| Hearing aids | Young children benefit from early fitting of hearing aids & speech training. |
Cochlear implantation | Children w/incomplete speech & sentence rehabilitation w/hearing aids & older persons w/severe-to-profound hearing loss: consider for cochlear implantation. |
Retinitis
pigmentosa
|
| Tunnel vision & night blindness can ↑ likelihood of accidental injury. |
Imbalance
| Vestibular rehabilitation | Neurologically active medications or sedatives can aggravate mild vestibular dysfunction. |
- 1.
Nadal & Iglesias [2018] describe the visual outcomes and rehabilitation of a one individual with USH2 that underwent Argus II prosthesis surgery.
Surveillance
Table 7.
Recommended Surveillance for Individuals with Usher Syndrome Type II
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System/Concern | Evaluation | Frequency |
---|
Hearing loss
| Audiometry & tympanometry w/hearing aids or cochlear implant to assure adequate auditory stimulation | Annually, incl testing w/hearing aids in place |
Cataracts
| Ophthalmologic eval | Annually from age 20 yrs or age of diagnosis |
Cystoid macular
edema
| Ophthalmologic eval |
Retinitis
pigmentosa
| Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, dark adapted rod perimetry), ERG, OCT, FAF | Annually from age 10 yrs or age of diagnosis |
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Usher syndrome type II (USH2) is inherited in an autosomal recessive manner.
Digenic inheritance and/or disease-modifier genes
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
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.
Prenatal Testing and Preimplantation Genetic Testing
Once the USH2-causing pathogenic variants have been identified in an affected family member, prenatal 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 Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Usher Syndrome Type II: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
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
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].
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.
Table 8.
Usher Syndrome Type II: Gene-Specific Laboratory Considerations
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Gene 1 | Special Consideration |
---|
ADGRV1
| Small & large deletions reported |
USH2A
| Multiple deep intronic pathogenic variants are known to occur in USH2A. Large single- & multiexon pathogenic variants have also been identified. |
- 1.
Genes from Table 1 in alphabetic order
Table 9.
Usher Syndrome Type II: USH2A Notable Pathogenic Variants
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Chapter Notes
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
23 December 2010 (me) Comprehensive update posted live
14 April 2009 (me) Comprehensive update posted live
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