Clinical characteristics.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Diagnosis/testing.

The diagnosis of USH1 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of six genes – MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2 – establishes the diagnosis if clinical features are inconclusive. Possible digenic inheritance has been reported in a few families.

Management.

Treatment of manifestations: In infants: an initial trial of hearing aids to stimulate residual hearing and accustom the infant to auditory stimulation. Cochlear implantation should be considered as young as medically feasible. Sign language and tactile signs (once visual loss occurs) for families who choose non-auditory communication. Specialized training from educators of the hearing impaired. Vestibular compensation therapy for children with residual balance function and sensory substitution therapy for individuals with complete absence of vestibular function. Standard treatments for retinitis pigmentosa.

Surveillance: Annual audiometry and tympanometry in those with cochlear implant or hearing aids to assure adequate auditory stimulation. Annual otoscopic exam with tympanometry in children with profound loss to evaluate for chronic otitis media. Annual ophthalmologic evaluation, fundus photography, visual acuity, visual field testing, electroretinography, optical coherence tomography, and fundus autofluorescence from age 20 years.

Agents/circumstances to avoid: Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution. 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.

USH1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Once the USH1-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible.

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 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 USH1 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP; therefore, the recommended molecular genetic testing approaches 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.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Hearing loss. The hearing loss in Usher syndrome type I (USH1) is congenital (i.e., present at birth), bilateral, severe-to-profound sensorineural hearing impairment (SNHI). While congenital SNHI should be identified through universal hearing screening at birth, occasionally false negative screening or missed screening before discharge to home results in delayed diagnosis until speech delay is obvious. Affected individuals do not develop speech unless fitted with cochlear implants. Hearing aids are usually inadequate in individuals with USH1 because of the severity of the hearing loss. Alternatively, sign language and tactile signs (once visual loss occurs) are communication options for families who choose nonauditory communication.

Imbalance. The imbalance in individuals with USH1 is associated with the deafness and is a defining feature of this disorder. While the timing and extent of "vestibular areflexia" is not fully understood, children with USH1 typically walk later than usual, at approximately age 18 months to two years. Older children may seem "clumsy" and experience frequent accidental injuries or have difficulty with activities requiring balance, such as riding a bicycle or playing sports.

Visual loss. Children with USH1 are often misdiagnosed as having nonsyndromic hearing impairment until delayed walking or tunnel vision and night blindness – early signs of retinitis pigmentosa (RP) – become severe enough to be noticeable, either by parents and teachers or by the individual. The onset of RP in individuals with USH1 is variable but can start in early infancy or childhood. RP is progressive, bilateral, symmetric photoreceptor degeneration of the retina that initiates in the midperiphery; 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, resulting in 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 USH1 age 30-40 years. Visual impairment worsens significantly each year [Pennings et al 2004]. Individuals with USH1 may become completely blind. Cataracts and/or cystoid macular edema sometimes reduce central vision. These two associated conditions are treatable.

Heterozygotes. Heterozygotes are asymptomatic.

Genotype-Phenotype Correlations

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

• c.1220delG. Audiometric screening of ten individuals of Yemenite Jewish ancestry revealed that individuals younger than age 40 years had normal hearing while older individuals showed mild-to-severe high-frequency hearing loss. This is the first report of individuals with USH1 and adult-onset hearing loss rather than congenital hearing loss [Khateb et al 2012].
• c.667G>T (p.Gly223Cys). Heterozygous variant reported in individuals with autosomal dominant nonsyndromic hearing impairment from a Korean cohort [Song et al 2020]

CDH23. A reduced frequency of null (e.g., nonsense, frameshift, splice) variants in CDH23 was observed in individuals with less severe phenotypes, with approximately 88%, 67%, and 0% of null variants found in persons with typical Usher type I (USH1D), atypical Usher syndrome, and nonsyndromic deafness type 12 (DFNB12), respectively [Bolz et al 2001, Bork et al 2001, Liu et al 2001, Astuto et al 2002, Bork et al 2002, Valero et al 2019].

PCDH15. Hypomorphic variants were associated with nonsyndromic hearing impairment indicating that residual function with some missense variants are sufficient for normal vision but not hearing, while more severe pathogenic variants result in USH1 [Ahmed et al 2001, Alagramam et al 2001, Ahmed et al 2003, Doucette et al 2009].

CIB2. To date all known pathogenic variants (copy number variants, splicing, indels, and missense) identified in CIB2 are associated with DFNB48, except one variant, c.192G>C (p.Glu64Asp), identified in four individuals from a single consanguineous Pakistani family with USH1J [Riazuddin et al 2012]. Booth et al [2018], however, reported three different loss-of-function variants in three families from diverse origins that cause DFNB48 (autosomal recessive nonsyndromic hearing loss) and not USH1.

Penetrance

Penetrance is complete in Usher syndrome type I.

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, presence or absence of vestibular areflexia, and age at onset of retinitis pigmentosa). The letters (e.g., USH1C, USH1B) indicate the molecular subtype with biallelic pathogenic variants in one of the related genes listed in Table 1.

Note: Gerber et al [2006] provide evidence that the USH1A locus does not exist; six of the nine families from the Bressuire region of France originally reported to map to this locus have been found to have pathogenic variants in MYO7A (USH1B).

Prevalence

In older publications the prevalence of Usher syndrome has been reported to range from 3.2 to 6.2 per 100,000. Usher syndrome was estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. Many of these estimates were made prior to 1989, when Möller et al [1989] subdivided Usher syndrome into Usher syndromes type I and II, and before the recognition of Usher syndrome type III. The specialized educational requirements of the congenitally deaf have historically rendered the population with Usher syndrome type I more accessible for study by researchers. Persons with Usher syndrome type II or Usher syndrome type III, who communicate orally and who are mainstreamed into regular schools, are not well represented in these estimates. It has been argued that the prevalence of Usher syndrome in the general population may therefore be substantially greater than estimated.

A recent study of children with hearing loss in Oregon found pathogenic variants in Usher syndrome-associated genes in 11% and estimated that the prevalence may be as high as one in 6,000 [Kimberling et al 2010].

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 in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.