Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy

Abstract

Autosomal recessive bestrophinopathy (ARB) and vitelliform macular dystrophy (VMD) are distinct phenotypes, typically inherited through recessive and dominant patterns, respectively. Recessively inherited VMD (arVMD) has been reported, suggesting that dominant and recessive BEST1-related retinopathies represent a single disease spectrum. This study compares adVMD, arVMD, and ARB to determine whether a continuum exists and to define clinical and genetic features to aid diagnosis and management. METHODS.One arVMD patient and nine ARB patients underwent standard ophthalmic examination, imaging, electrophysiology, and genetic assessments. A meta-analysis of reported BEST1 variants was compiled, and clinical parameters were analyzed with regard to inheritance and phenotype.RESULTS. Among 10 patients with biallelic BEST1 variants, three novel ARB variants (p.Asp118Ala, p.Leu224Gln, p.Val273del) were discovered. A patient with homozygous p.Glu35Lys was clinically unique, presenting with VMD, including hyperautofluorescence extending beyond the macula, peripheral punctate lesions, and shortened axial-length. A tritan-axis color vision deficit was seen in three of six (50%) of ARB patients. Attempts to distinguish recessively-inherited ARB and dominantly-inherited VMD genotypically, by variant frequency and residue location, did not yield significant differences. Literature meta-analysis with principle component analysis of clinical features demonstrated a spectrum of disease with arVMD falling between adVMD and ARB.CONCLUSIONS. This study suggests that arVMD is part of a continuum of autosomal recessive and dominant BEST1-related retinopathies. Detailed clinical and molecular assessments of this cohort and the literature are corroborated by unsupervised analysis, highlighting the overlapping heterogeneity among BEST1-associated clinical diagnoses. Tritan-axis color vision deficit is a previously unreported finding associated with ARB.

Paradoxical autosomal recessive bestrophinopathy-like phenotypes shown in an autosomal dominant pedigree

“…BVMD is usually thought as an autosomal dominant (AD) disorder caused by a single mutation in the BEST1 gene although there were reports about arVMD. 3 Classic BVMD presents with central vitelliform lesions. ARB can be caused by either compound heterozygous or homozygous mutations in the BEST1 gene as an autosomal recessive disorder.…”

Clinical Correlation Between Optical Coherence Tomography Biomarkers and Retinal Sensitivity in Best Vitelliform Macular Dystrophy

“… 1 – 3 It is most frequently caused by dominant variants, even though a vitelliform phenotype can also be inherited recessively. 4 , 5 Phenotypical heterogeneity is a hallmark of BVMD, and its natural history has been described by Gass. 6 The early stage of the condition generally takes the form of a round/oval central yellow lesion caused by the accumulation of lipofuscin-like material, which is gradually reabsorbed over the follow-up and develops into subretinal fibrosis and atrophy.…”

Anatomical and functional outcomes of bevacizumab treatment in pediatric autosomal recessive bestrophinopathy

“…1 The estimated prevalence of ARB is 1:1,000,000; although the age of onset is between 4 and 40 years, most cases begin in childhood. 1,2 Clinically, ARB presents with multifocal subretinal yellowish deposits involving the posterior pole corresponding to marked hyperautofluorescence on fundus autofluorescence (FAF). Other abnormalities such as accumulation of subretinal fluid, cystoid macular edema, and choroidal neovascularization have been described.…”

“…4,5 Unfortunately, most patients with ARB end up with low vision because of choroidal neovascularization or RPE atrophy. 2,5 In an era where multimodal imaging and genetic testing allows early diagnosis, early intervention could alter the unfortunate fate of photoreceptors affected by this disease. Therefore, in the present study, we report anatomical and functional outcomes of anti-VEGF treatment in four eyes with ARB and discuss the dilemma of anti-VEGF intervention in the absence of proven therapies for this blinding disorder.…”

“…Other abnormalities such as accumulation of subretinal fluid, cystoid macular edema, and choroidal neovascularization have been described. 3 In addition, ARB patients usually have other ocular associations, including hyperopia, short axial length, and shallow anterior chambers with an increased risk of acute angle-closure glaucoma. 4,5 Unfortunately, most patients with ARB end up with low vision because of choroidal neovascularization or RPE atrophy.…”