Autosomal Recessive Bestrophinopathy-Phenotypic Variability, Natural History, and Genotype-Phenotype Correlations

To describe the clinical characteristics, natural history, and genotype-phenotype correlations of autosomal recessive bestrophinopathy (ARB).

Retrospective cohort study including data collected for clinical practice.

Thirty-four consecutive patients (68 eyes) affected by ARB who had a molecularly confirmed diagnosis followed at a single referral center for inherited retinal diseases (REFERET, Quinze-Vingts Hospital, Paris, France).

We collected data from medical records, including genetic data, ophthalmologic history, clinical examinations, retinal imaging, and full-field electroretinograms (ERG). Disease severity graded on short-wavelength autofluorescence (SW-AF), and the presence of primary angle closure (PAC) was evaluated as candidate risk factors for clinical outcomes. Longitudinal outcome analysis was performed using mixed-effects linear modeling and Kaplan-Meier survival curves.

ERG amplitudes; best-corrected visual acuity and degree of visual impairment according to World Health Organization criteria; central subfield thickness measured on optical coherence tomography.

The median age at baseline was 32 years (interquartile range, 18.3-46.9), and 29% (10/34) of patients had PAC. On SW-AF, 21% (7/34) had isolated macular lesions (grade 1), 44% (15/34) had multifocal lesions or diffuse alterations at the posterior pole with zonal sparing (grade 2), and 35% (12/34) had panretinal alterations (grade 3). Marked attenuation of ERG amplitudes was found only in patients with grade 3 disease. Of 32 unique BEST1 variants, 11 (34%) were novel, and the p.(Thr363Pro) occurred only in grade 1 disease. The median age at onset of severe visual impairment was lower in patients with PAC (47 years) compared with those without (68 years; P = .01), whereas no such association was observed with SW-AF grade. No significant linear annual change in best-corrected visual acuity could be demonstrated over a median follow-up of 3 years.

ARB encompasses a wide phenotypic spectrum, ranging from mild, isolated macular involvement to severe panretinal degeneration with abnormal ERG. However, the risk of visual impairment appears to be driven primarily by the presence of PAC rather than by the severity of fundus lesions, representing an important confounding factor for future clinical trials. The very slow rate of visual acuity decline further underscores the need for more sensitive functional outcome measures in bestrophinopathies.