Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies

Abstract

Purpose: To analyse the spectrum of clinical features and molecular genetic data in a series of patients carrying likely disease-associated variants in the BEST1 gene. Methods: Retrospective observational analysis of clinical data extracted from the medical records of visual function, multimodal imaging and electrophysiology of 62 eyes of 31 patients. Molecular genetic analysis was performed by means of panel-based NGS or Sanger sequencing. Results: The spectrum of variants in the BEST1 gene comprised 19 different variants and three of which are novel. Fundus photographs and OCT images allowed categorization of 52 eyes as Best vitelliform macular dystrophy (BVMD) with stages 1 to 5 and 10 eyes with autosomal recessive bestrophinopathy (ARB), with more severe phenotype. One patient was shown to be heterozygous for a variant, which has so far been described only in ARB, but this patient had the BVMD phenotype. There was no significant progression of the visual acuity during the follow-up period of 5 years both in BVMD and ARB. The most prevalent pattern of fundus autofluorescence (FAF) in BVMD was 'patchy'. There were diverse visual field defects in static automated perimetry (SAP) depending on the stage. The Arden ratio was significantly lower in ARB patients and in eyes with stage 5 of BVMD. Conclusions: The genotype does not always predict the phenotype in patients with BVMD and ARB; however, having two mutations in the BEST1 gene causes a more severephenotype.FAFhelpedtodistinguishARBfromBVMD.Mostoftheobserved eyesdidnotprogressfunctionallyduringthefollow-up.ARBandtheatrophicstageof BVMD as the disease end-stage had the worst visual functions and EOG results.

Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes

“…21 Patients with Best disease (BEST1) can maintain good BCVA over time, often showing no significant differences between baseline and follow up acuity in longitudinal studies. 22,23 On the other hand, individuals with recessive ABCA4-related Stargardt disease, often lose three or more ETDRS lines over 10 years. 24 A challenge that AD conditions face is that haploinsufficiency is rarely their mechanism of disease.…”

Elaborate Evaluation of Farnsworth Dichotomous D-15 Panel Test Can Help Differentiate between Best Vitelliform Macular Dystrophy and Autosomal Recessive Bestrophinopathy

“…Bestrophinopathies, including BVMD and ARB, usually manifest as a reduction in the VA in the first or second decade of life. However, these diseases show a large variation in expressivity [ 10 , 22 ], also in colour vision.…”

“…Colour vision was assessed using the saturated Farnsworth Panel D-15 and the Desaturated Lanthony Panel D-15 test at a distance of 50 cm with near correction. Both tests were performed for each eye separately; the results of both eyes were taken into consideration, as there is often an asymmetry found between the eyes during the course of the disease [ 22 ].…”

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation

“…Over time, the vitelliform lesion can lead to a vitelliruptive stage, where breakdown of the vitelliform lesion will generate irregular yellow deposits. This deposition, mostly lipofucsin and melanofucsin granulae [10] within the retinal pigment epithelium (RPE), the subretinal space, and the photoreceptor zone can cause a break in the RPE/Bruch's membrane and a later complication on the choroidal neovascular membrane (CNVM) [11]. Finally, in the atrophic stage, there is a RPE death and loss of photoreceptor cells, leading to widespread geographic atrophy with progressive and irreversible retinal cell loss and the consequent VA decline [7,12,13].…”