Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile

Abstract

Background: Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. Methods: Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. Results: The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G > A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. Conclusions: We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB. Our findings helped improve the understanding of ARB mechanisms.

BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity

“…The visual acuity of Family 3 proband was recovered to 1.0 after anti-VEGF treatment for CNV in the right eye, and no significant decrease in visual acuity was seen after six months of follow-up, which is consistent with previous reports in the literature (Hussain et al, 2015). For ARB patients who are complicated with macular edema, oral administration of Methazolamide may help to reduce such macular edema; Panpan Ye et al (2020) found a significant decrease in the levels of certain metabolites, such as citric acid, L-threonine, and eicosapentaenoic acid, in the blood of ARB patients and found significant improvement in macular edema after long-term supplementation of citric acid in these patients. In recent years, research on the treatment of Bestrophinopathies has yielded fruitful results and it will surely usher in a promising spring.…”

Twelve-year follow up of a case of autosomal recessive bestrophinopathy with transient resolution of retinal edema in one eye

“…Our report is the first case described in the literature that showed a transient resolution of ME without medical treatment and dietary therapy, contrary to the report of Ye et al which demonstrated an improvement of macular edema after three months of treatment with lemonade. 7 Moreover, our finding is unexpected considering the series of cases reported in the literature, which revealed slow progressive vision loss, reduction of central macular thickness, stability of SRF, worsening of ERG response and cone photoreceptor loss. 1,3,9…”

“…This is the first case of ARB reported in the literature with a resolution of ME with dietary theraphy. 7 In our case, a transient resolution of macular was achieved in the OD during two months. Nonetheless, our patient denied recent changes in his alimentary habits, so we suggested that an undetected metabolic or hormonal change may be involved in this finding.…”

“…Its clinical phenotype includes hypermetropia, shallow anterior chamber that predispose to angle closure glaucoma, amblyopia, characteristic retinopathy consisting of multiple yellowish flecks, central visual loss from macular edema (ME), and a reduced ERG. [1][2][3]7,9 Clinical phenotype resulting from mutations in the BEST1 gene is variable, probably because mutations in this gen could affect the chloride channel function of bestrophin1 and/or the calcium channel activity. 10 Mainly, genotype-phenotype correlation depends on molecular characteristics of causal mutations.…”

“…Nevertheless, fundus features vary among patients. 1,3,7 Electrophysiological characteristics consist of reduced cones and rods responses in fullfield electroretinography (ERG) and severely decrease of light peak to dark rough ratio in electrooculogram (EOG). 3,8 We report the multimodal imaging findings throughout 12 years of follow-up in a case of ARB.…”