Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome: A Retrospective Case Series

Patient Information

This retrospective case series involved 28 patients (15 females, 13 males) with molecularly confirmed USH1C-associated retinopathy evaluated at a tertiary referral center from January 1989 through February 2024. The mean age was 27.0 years (standard deviation [SD] 12.2; range, 7-58 years). Most patients were young adults presenting primarily with nyctalopia and peripheral vision difficulties. There was no detailed data on ethnic background or familial consanguinity. The cohort included 18 patients homozygous for USH1C pathogenic variants, and two novel variants were identified during molecular analysis.

Diagnosis

The diagnosis of USH1C-associated Usher syndrome was confirmed via detection of pathogenic variants in the USH1C gene molecularly. Clinically, patients presented predominantly with symptoms consistent with retinitis pigmentosa (RP), including night blindness (nyctalopia) in 92.3% (24/26) and peripheral vision impairment in 82.1% (23/28). Retinal examination and imaging demonstrated characteristic RP findings, confirmed by visual field testing indicating constriction. Optical coherence tomography (OCT) revealed variable central retinal changes including cystoid macular edema in some cases.

Best-corrected visual acuity (BCVA) at baseline in the better-seeing eye (n=25) averaged 0.22 logMAR (~20/32 Snellen). Among 15 patients with ≥5 years follow-up, BCVA declined from 0.30 logMAR (20/40) to 0.59 logMAR (20/80) over time. The retinal degeneration was localized to specific areas in patients harboring particular missense variants (c.308G>A [p.Arg103His] and c.440A>G [p.His147Arg]) sparing the superior retina. Four of 24 patients (16.7%) met World Health Organization criteria for severe sight impairment (visual acuity 20/200 or worse in the better-seeing eye). Depression and unemployment rates, assessed via patient questionnaires and general practitioner records, were notable comorbidities.

Differential Diagnosis

The primary consideration was retinitis pigmentosa of other genetic etiologies. Differential diagnoses included:
– Other Usher syndrome subtypes (USH1B, USH2, USH3) differentiated by genetic testing and phenotypic presentations.
– Non-syndromic retinitis pigmentosa without hearing loss.
– Other causes of progressive retinal dystrophy such as Leber congenital amaurosis or cone-rod dystrophies.
– Acquired retinal degenerations (e.g., toxic retinopathy) were less likely given hereditary pattern.
– Syndromic conditions presenting with hearing impairment and retinal degeneration, such as Alström syndrome, were excluded by genetic analysis.

Molecular confirmation of USH1C variants effectively ruled out these alternatives.

Treatment and Management

Management during this study period was primarily supportive and symptomatic. Interventions included:
– Routine ophthalmologic monitoring including BCVA, visual fields, and retinal imaging.
– Treatment of cystoid macular edema (CME) in affected patients; details on specific treatments used (e.g., carbonic anhydrase inhibitors, corticosteroids) were not specified.
– Audiological evaluation and provision of hearing aids or cochlear implants as applicable.
– Psychosocial support recognizing elevated rates of depression (38.5% of surveyed patients) and unemployment (30.4%), highlighting the necessity for integrated counseling and vocational rehabilitation.

No disease-modifying or gene therapies were reported during the study period, though the slow progression suggests an opportunity for future therapeutic intervention.

Outcome and Prognosis

USH1C-associated retinopathy demonstrated a slow but progressive decline in visual function over decades, with BCVA decreasing on average by approximately 0.53 Early Treatment Diabetic Retinopathy Study (ETDRS) letters per year. Cystoid macular edema persisted in some patients but did not significantly increase retinal thickness over time. Despite gradual vision loss, a proportion (16.7%) developed severe sight impairment.

The early onset of sensory symptoms and the progressive nature of visual and auditory deficits result in considerable social morbidity, including depression and unemployment. These findings emphasize the importance of multidisciplinary long-term care and tailored counseling regarding prognosis. The slow disease progression underscores the potential for emerging therapies to preserve function if initiated early.

Discussion

This case series enhances understanding of the phenotypic spectrum and natural history of USH1C-associated Usher syndrome, a ciliopathy characterized by congenital profound hearing loss and progressive retinal degeneration due to pathogenic variants in the harmonin gene (USH1C). The identification of two novel pathogenic variants expands the mutational spectrum. The predominance of symptoms such as nyctalopia and peripheral vision loss reflects rod photoreceptor dysfunction typical of RP.

The relatively slow visual acuity decline observed highlights a window for therapeutic intervention. The differential retinal involvement related to specific missense variants suggests genotype-phenotype correlations that may inform prognosis and targeted treatment strategies.

Psychosocial findings of elevated depression and unemployment illustrate the broader social impact of dual sensory impairment in Usher syndrome, underscoring the need for comprehensive multidisciplinary care including mental health and vocational support.

Current therapies remain supportive, but gene therapy and other molecular approaches under investigation could benefit from these detailed natural history data to inform clinical trial design and patient counseling.

The study’s strengths include a large, genetically confirmed cohort followed over extended periods. Limitations relate to retrospective design and incomplete data on some social outcomes.

In conclusion, USH1C-associated retinopathy presents early with night blindness and peripheral vision loss, progressing slowly with measurable functional decline. Genetic characterization assists diagnosis and prognostication. The social burden necessitates holistic care. These insights contribute to the evolving landscape of precision medicine in inherited retinal dystrophies.

References

Aychoua N, de Guimarães TAC, Ponnekanti MB, Sasidharan S, Leung SP, Ibukun FA, James N, Berry V, Mahroo OA, Webster AR, Kalitzeos A, Michaelides M. Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome. JAMA Ophthalmol. 2025 Nov 26. doi:10.1001/jamaophthalmol.2025.4813. Epub ahead of print. PMID: 41296346.

Additional references for background:
– Weil D, Blanchard S, Kaplan J, et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature. 1995;374(6517):60-61.
– Smith RJH, Bale JF, White KR. Sensorineural hearing loss in children. Lancet. 2005;365(9462):879-890.
– Kimberling WJ, Mckenna MJ. Usher syndrome: clinical and molecular genetics. J. Invest. Dermatol. Symp. Proc. 1995;1(2):147-150.