A unique case series of autosomal recessive bestrophinopathy exhibiting multigenerational inheritance.

INTRODUCTION: Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance.

METHODS: Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives.

RESULTS: The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son's examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473G>A/c.473G>A (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473G>A/WT (p.R218H/WT).

DISCUSSION: We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.