A novel founder variant in BEST1 gene causing autosomal recessive bestrophinopathy.

backgroundAutosomal recessive bestrophinopathy (ARB) is a rare retinal dystrophy caused by homozygous or compound heterozygous null variants in the BEST1 gene. Clinically, ARB presents with variable features including central visual impairment, global photoreceptor dysfunction (as indicated by abnormal full-field ERG), and a significantly reduced electro-oculogram (EOG) light rise, a hallmark of bestrophinopathy. Fundus examination reveals widespread retinal pigment epithelial (RPE) disturbance, vitelliform deposits in the posterior pole (more clearly visualized with fundus autofluorescence), and macular fluid accumulation. Angle-closure glaucoma, secondary to anterior chamber dysgenesis, is a potential complication. This work aims at documenting the founder effect of a novel variant in the BEST1 gene causing autosomal recessive bestrophinopathy and determining its variable clinical features.

methodsTwelve members of nine unrelated, consanguineous Egyptian families with a history of impaired central vision underwent comprehensive ophthalmological examination, fundus color photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) of the macula, and electrophysiological studies. Variant screening of coding exons of the BEST1 gene and some flanking regions was performed using the Sanger sequencing technique. The pathogenicity of the variants was tested using different in silico functional analysis tools.

resultsThe clinical examination and investigations confirmed the ARB phenotype. All twelve patients exhibited (c.365 G > C, p. Arg122Pro) a novel BEST1 gene variant in a homozygous form. On top of the classical retinal phenotype of ARB, some patients had other ocular associations: four patients were found to have angle-closure glaucoma, one patient had associated corneal dystrophy, one developed a macular hole, and one patient developed uveitis.

conclusionThe identification of the same, novel homozygous BEST1 missense variant in twelve patients from nine unrelated, consanguineous families of Egyptian origin, suggests a founder effect. Angle-closure glaucoma was the most commonly associated ocular abnormality (30%). Our finding expands the molecular spectrum of ARB-associated variants, and identification of this founder variant can simplify genetic testing in the presence of limited resources and lead to better counseling.