#JAMAClinicalUpdate: BEST1-One Gene, Many Diseases
Retinal dystrophies associated with the gene BEST1, collectively known as best bestrophinopathies, are phenotypically heterogeneous. Although best vitelliform macular dystrophy (BVMD) is the most common bestrophinopathy, the distinct clinical conditions encompassed by the bestrophinopathies vary in features, including the mode of inheritance and degree of macular vs peripheral retinal involvement.

In the recent issue of JAMA Ophthalmology, the characteristic features of ARB, which was recognized as resulting from biallelic sequence variants in BEST1 in 2008, include bilateral serous retinal detachments extending through the posterior pole, numerous small vitelliform deposits, cystoid cavities on optical coherence tomography, and fibrotic-appearing deposits suggesting prior choroidal neovascularization. The relative enrichment of ARB in this cohort permits several observations. As previously noted, overall retinal function as assessed by full-field electroretinogram can vary from normal to significantly impaired in ARB even among individuals with the same genotype. Shah et al1 also describe a novel observation of a beaten metal appearance to the peripheral retina in most patients who undergo widefield fundus photography.

The clinical relevance of this finding remains unclear, and its presence was not consistently associated with electroretinogram findings. The role of genetic testing in reaching an accurate diagnosis was also recently highlighted in a cohort of patients with autosomal dominant vitreoretinochoroidopathy in whom atypical phenotypic features had resulted in initial diagnoses of cone-rod dystrophy and RP.6 Fundamental questions still remain to be addressed regarding the pathophysiology of the bestrophinopathies even as knowledge of the clinical spectrum of disease is refined. As noted by the authors, questions remain regardingmissense sequence variants reported in the literature in association with BVMD and ARB.

The importance of understanding disease mechanisms is increasingly relevant as efforts to develop therapies continue. The recent description of different intracellular mechanisms for the recognition and degradation of the spatially intermingled missense sequence variants that can result in loss of function in ARB vs a dominant-negative effect seen in BVMD may also provide a target for therapeutic intervention.

Source: https://jamanetwork.com/journals/jamaophthalmology/article-abstract/2763867