Hae Rang Kim, Jinu Han, Yong Joon Kim, Hyun Goo Kang, Suk Ho Byeon, Sung Soo Kim, and Christopher Seungkyu Lee | Genes | 4 July 2022 | 13(7) | pg. 1197 | https://doi.org/10.3390/genes13071197
Abstract
Autosomal recessive bestrophinopathy (ARB) is a rare subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene. ARB is characterized by multifocal subretinal deposits accompanied by macular edema or subretinal fluid, hyperopia, co-existing narrow angle, and a marked decrease in electrooculogram. However, little is known about the genetic variants and specific clinical features of ARB. This is an observational case series of patients with a clinical and genetic diagnosis of ARB who underwent multimodal imaging. We describe ten patients from nine unrelated families with six known variants and three novel missense variants: c.236C→T, p.(Ser79Phe); C.452C→T, p.(Leu151Pro); and c.650C→T, p.(Trp217Met). The most common variant was c.584C→T, p.(Ala195Val), observed in six patients, without correlation to the severity of the phenotype. All patients manifested bilateral multifocal subretinal deposits and subretinal fluid throughout the follow-up period, while intraretinal fluid was found in approximately half of the eyes. The extent or chronicity of the fluid collection did not correlate with visual acuity. Angle-closure glaucoma was present in five eyes. Three patients had a genetically confirmed family history of ARB, and one patient had a clinically suspected family history. This study reveals novel mutations in the BEST1 gene and adds to the spectrum of clinical presentations of ARB.
1. Introduction
Bestrophinopathy is a spectrum of inherited macular degenerations caused by mutations in the BEST1 gene [1]. BEST1 is located on chromosome 11q13 [2,3] and encodes bestrophin-1, a 585 amino-acid calcium-activated Cl− channel localized to the basolateral membrane of retinal pigment epithelium (RPE) [4]. Mutation in the BEST1 gene might result in abnormal functioning of the protein bestrophin-1, an anion channel in the RPE, leading to a variety of retinopathies [5,6]. The most prevalent variant, Best vitelliform macular dystrophy [VMD, also known as Best disease; Online Mendelian Inheritance in Man identifier (OMIM), 153700], is characterized by prominent central macular lesions that undergo consecutive morphologic changes from characteristic ‘egg-yolk’ appearance in the vitelliform stage to vitelliruptive stage, pseudohypopion state, and atrophic stage [7]. Since the first report in 1905 by Friedrich, a wide array of missense mutations in BEST1 variants have been reported [8]. Other subtypes include adult-onset vitelliform macular dystrophy (OMIM 153840), autosomal dominant vitreoretinochoroidopathy (OMIM 193220), retinitis pigmentosa 50 (OMIM 613194), and autosomal recessive bestrophinopathy (OMIM 611809) [7].
In 2006, Schatz et al. first reported two related patients with multifocal vitelliform dystrophy and compound heterozygous BEST1 variants. Burgess et al. then denominated the term “autosomal recessive bestrophinopathy” (ARB) as a new BEST1-associated phenotype. Unlike missense mutations in autosomal dominant inheritance of VMD, ARB is caused by a homozygous or compound heterozygous BEST1 mutation with a modifier effect of the first on the second mutation in the latter [9,10]. ARB is characterized by multifocal diffuse subretinal deposits that appear hyperfluorescent on fundus autofluorescence imaging, accompanied by macular edema or subretinal fluid, hyperopia, and co-existing narrow angle. Electrophysiological characteristics include a marked decrease in light rise on electrooculography (EOG) and relatively preserved electroretinography (ERG) parameters unless photoreceptor cells are severely damaged. Although abnormal EOG findings are crucial for the diagnosis of bestrophinopathy, mutation analysis is necessary to confirm the diagnosis of a specific subtype of bestrophinopathy.
The prevalence of ARB is estimated to be 1/1,000,000 [9]. In Korea, only two patients with ARB from a single family were reported in 2015 [11]. Herein, we report on ten patients with ARB due to mutations in BEST1, characterizing their clinical features and genetic mutations.
References
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