Best Disease: Review of reported causing mutations, genotype-phenotype correlation, and prevalence analysis in the Israeli population

Abstract

Purpose : To review all reported Best disease causing mutations, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population.

Methods : Medical records of patients with Best disease, adult-onset vitelliform macular dystrophy (AVMD), and bestrophinopathy were collected over the last 20 years from most tertiary medical centers in Israel. Clinical data included eye examination, fundoscopy, visual acuity, refraction, electroretinography (ERG), electrooculography (EOG) and optical-coherence tomography images. Mutation analysis on patients was performed by candidate gene analysis and whole exome sequencing. Mutation data was collected from Pubmed, HGMD, LOVD and were analyzed using manually written code on R-studio and QSIG. Disease prevalence was calculated in the Israeli population with 9.656 million residents.

Results : A total of 116 Israeli subjects were diagnosed with Best disease (87 patients), AVMD (16) or AR bestrophinopathy (13), according to fundoscopic findings, ERG and EOG. Based on the estimated population size of 9.656 million citizens, the minimal prevalence of Best disease in Israel is 1:83,333, with higher prevalence in the Arab-Muslim population (1:59,172) compared to the Jewish population (1:90,909). The genetic cause of the disease was identified in 83 patients (72%), mainly with autosomal dominant inheritance due to BEST1 (21 mutations), PRPF2 (4 mutations), and IMPG2 (1 mutation) genes.
In addition, we collected information on all reported BEST1 mutations and analyzed their distribution along bestrophin. The analysis revealed conserved regions in 3 out of the 4 trans-membrane domains and in the intracellular domains only in areas within close proximity to the trans-membrane domains. Those conserved areas include 78% of the dominant missense mutations (p-value < 0.001). No correlation was identified between amino acid conservation and the age of onset.

Conclusions : We showed here that the prevalence of Best disease in Israel is similar to the one reported in Sweden (1.5:100,000) and lower than the reported one in USA, and the prevalence of AVMD is much lower than was reported previously in USA (1:7,400-1:8,200 ). The conserved amino acids located mainly in the transmembrane domains and intracellular regions are extremely crucial for normal protein folding and function.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.