Usher syndrome

Usher syndrome is a clinically and genetically heterogeneous disorder affecting the auditory, vestibular, and ocular systems, and represents the most frequent genetic cause of concurrent deaf-blindness. Three clinical subtypes are distinguished by the severity, onset, and progression of sensory involvement.

Type I (USH1) presents with congenital, bilateral, severe-to-profound sensorineural hearing impairment and vestibular areflexia; affected children typically walk later than expected, at approximately 18 months to 2 years of age, and retinitis pigmentosa manifests in infancy or childhood.

Type II (USH2) is defined by congenital, moderate-to-severe sloping sensorineural hearing loss predominantly affecting higher frequencies, generally intact or variably reduced vestibular function, and retinitis pigmentosa with onset in late adolescence or early adulthood.

Type III (USH3) shows postlingual progressive hearing loss, variable vestibular impairment, and late-onset retinal disease. The retinitis pigmentosa is progressive, bilateral, and symmetric, beginning with rod-mediated night blindness and constricted visual fields, followed by cone degeneration and eventual central vision loss.

A study using large genomic databases in multiple populations worldwide reported the prevalence of Usher syndrome across all subtypes to be 1/29,000.

Usher syndrome is inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers; the recurrence risk for siblings is 25% in each pregnancy. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Suggestive clinical findings are confirmed by audiometric testing (pure tone audiometry, otoacoustic emissions, auditory brainstem response), vestibular assessment (rotary chair, videonystagmography, vestibular evoked myogenic potentials), and ophthalmologic evaluation including fundus photography, electroretinography, optical coherence tomography, visual field testing, and fundus autofluorescence. Because no single biochemical or imaging marker establishes the diagnosis, definitive confirmation rests on molecular genetic testing identifying biallelic pathogenic variants in one of the associated genes.

Main differential diagnoses include:

• Nonsyndromic sensorineural hearing loss (with or without coinherited nonsyndromic retinitis pigmentosa): sensorineural hearing loss without vestibular areflexia and without retinitis pigmentosa, frequently the initial diagnosis until retinal disease emerges; GJB2, MYO7A, USH2A, CDH23, PCDH15, and others
• : sensorineural hearing loss with progressive cone-rod dystrophy, childhood obesity, hyperinsulinaemia, type 2 diabetes, cardiomyopathy, and progressive multiorgan fibrotic involvement; ALMS1
• Refsum disease: retinitis pigmentosa as the leading feature, with anosmia, polyneuropathy, ataxia, and mild-to-moderate sensorineural hearing loss driven by phytanic acid accumulation; PEX7, PHYH

• Establishing the diagnosis through identification of the underlying pathogenic variant(s).
• Enabling specific and individualised surveillance and clinical management as a prerequisite for targeted medical care, decided by the treating physicians in consultation with the affected individual.
• Identifying at-risk family members through targeted variant testing once the familial pathogenic variants have been characterised.

• Koenekoop RK, Arriaga MA, Trzupek KM, Lentz JJ. Usher syndrome type I. 2020 Jun 25. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301442.
• Koenekoop R, Arriaga M, Trzupek KM, Lentz J. Usher syndrome type II. 2020 Oct 22. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301515.
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• Smirnov VM, Nassisi M, Mohand-Saïd S, Bonnet C, Aubois A, Devisme C, et al. Retinal phenotype of patients with CLRN1-associated Usher 3A syndrome in French Light4Deaf cohort. Invest Ophthalmol Vis Sci. 2022;63(4):25. doi:10.1167/iovs.63.4.25. PMID:; PMCID: PMC9055553.
• Redfield SE, Mauriac SA, Geleoc GS, Shearer AE, et al. A genomic analysis of Usher syndrome: population-scale prevalence and therapeutic targets. Am J Med Genet C Semin Med Genet. 2025;199:218-27. doi:10.1002/ajmg.c.32142. PMID:; PMCID: PMC12353266.