Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome

Expanding insight into the phenotypic spectrum, social burden of dual sensory impairment, and progression of USH1C-associated retinopathy is essential to inform prognosis and guide emerging therapies.

To characterize some genetic variants, clinical features, natural history, and social outcomes of USH1C-associated retinopathy in a patient cohort.

This was a retrospective case series including patients with molecularly confirmed UCH1C-associated retinopathy evaluated at a tertiary referral center from January 1989 to February 2024.

Molecularly confirmed pathogenic variants in USH1C.

Main outcomes included best-corrected visual acuity (BCVA) measured with the Snellen chart, retinal imaging features, genetic variants, and patient-reported social outcomes. Depression was documented by general practitioners using the Patient Health Questionnaire 9. Unemployment was self-reported at last follow-up. Retinitis pigmentosa diagnosis (RP) was diagnosed based on characteristic retinal findings and visual field loss.

A total of 28 patients (mean [SD] age, 27.0 [12.2] years; range, 7-58 years; 15 female [53.6%]) were included in this analysis. Two novel pathogenic USH1C variants were identified; 18 patients were homozygous. Presenting symptoms included nyctalopia (24 of 26 patients [92.3%]) and peripheral vision difficulties (23 of 28 patients [82.1%]). Baseline BCVA (Snellen chart) in the better-seeing eye (n = 25) was 0.22 logMAR (20/32). Among 15 patients with follow-up of 5 years or more, baseline BCVA was 0.30 logMAR (20/40), declining to 0.59 logMAR (20/80). In Early Treatment Diabetic Retinopathy Study (ETDRS) equivalents (n = 15), decline averaged 0.53 letters per year (median, 0; range, 0-2). Four of 24 patients (16.7%) met World Health Organization criteria for severe sight impairment (20/200 or worse in the better-seeing eye). Depression was reported by 5 of 13 patients (38.5%) and unemployment by 7 of 23 patients (30.4%). Optical coherence tomography revealed cystoid macular edema in 5 of 21 patients at baseline, persisting in 2 patients at follow-up. Mean (SD) central subfield thickness was 260.6 (53.6) µm at baseline (n = 18) and 259.4 (44.5) µm at follow-up (n = 15). Patients with missense variants c.308G>A (p.Arg103His) and c.440A>G (p.His147Arg) showed retinitis pigmentosa sparing the superior retina.

Results of this case series study suggest that USH1C-associated retinopathy was characterized by slow decline of visual acuity and modest ellipsoid zone loss over decades. Depression and unemployment were also observed, with implications for prognosis and counseling. Early onset and slow progression highlight its potential as a target for emerging therapies.