Detailed Clinical, Ophthalmic and Genetic Characterization of ADGRV1-Associated Usher syndrome.

PURPOSE: To present the clinical characteristics, retinal features, natural history, and genetics of ADGRV1-Usher syndrome (USH).

DESIGN: Multicenter international retrospective cohort study.

METHODS: Review of clinical notes, hearing loss history, multi-modal retinal imaging, and molecular diagnosis. Thirty patients (28 families) with USH type 2 and disease-causing variants in ADGRV1. Visual function, retinal imaging and genetics were evaluated and correlated; with retinal features also compared to those of the commonest cause of USH type 2, USH2A-USH.

RESULTS: The mean age at the first visit was 38.6 ± 12.0 years old (range 19 - 74 years) and the mean follow-up time was 9.0 ± 7.7 years. Hearing loss was reported in the first decade of life by all patients, 3 (10%) described progressive loss, and 93% had moderate-severe impairment. Visual symptom onset was at 17.0 ± 7.7 years of age (range 6 - 32 years), with 13 patients noticing problems before the age of 16. At baseline, 90% of patients had no or mild visual impairment. The most frequent retinal features were a hyperautofluorescent ring at the posterior pole (70%), perimacular patches of decreased autofluorescence (59%), and mild-moderate peripheral bone-spicule-like deposits (63%). Twenty-six (53%) variants were previously unreported, 19 families (68%) had double-null genotypes, and 9 were not-double-null. Longitudinal analysis showed significant differences between baseline and follow up central macular thickness (CMT, -1.25 µm/year), outer nuclear layer thickness (-1.19 µm/year), and ellipsoid zone (EZ) width (-40.9 µm/year). The rate of visual acuity decline was 0.02 LogMAR (1 letter)/year and the rate of constriction of the hyperautofluorescent ring was 0.23 mm2 /year.

CONCLUSIONS: ADGRV1-USH is characterized by early-onset, usually non-progressive, mild to severe hearing loss and generally good central vision until late adulthood. Perimacular atrophic patches and relatively retained EZ and CMT in later adulthood are more often seen in ADGRV1- than in USH2A-USH.