Autosomal recessive bestrophinopathy (ARB) is a monogenic retinal dystrophy caused by biallelic pathogenic variants in the BEST1 gene, encoding the bestrophin-1 chloride channel critical for retinal pigment epithelium (RPE) ion homeostasis. While ARB is considered a null phenotype due to complete loss of functional protein, clinical manifestations exhibit substantial phenotypic heterogeneity, challenging assumptions about genotype–phenotype uniformity. This study presents a detailed analysis of the genetic architecture and clinical diversity in 27 genetically confirmed ARB patients from a single tertiary referral center, revealing insights into variant distribution, functional impact, and the spectrum of disease expression.
All patients underwent molecular testing via Sanger sequencing or targeted next-generation sequencing, with some variants identified through whole-genome sequencing initiatives. Biallelic pathogenic variants were detected in every genotyped proband, including 19 compound heterozygotes and 8 homozygotes. A total of 31 unique rare variants were identified across 54 alleles, comprising 18 missense, 9 protein-truncating, 2 canonical splice-site mutations, one in-frame deletion (12 nucleotides), and one multi-exon deletion. The most recurrent variant was c.422G>A, p.(Arg141His), found in four unrelated individuals, suggesting potential founder effects or selective pressure at this residue. Nine novel variants were reported, including five novel missense and four truncating mutations, all absent from gnomAD v2.1.1 and not previously documented in ClinVar.
Pathogenicity assessment using CADD PHRED scores demonstrated that ARB-associated missense variants had significantly higher pathogenicity scores than those in the general population (p < 0.001), supporting their deleterious nature. Spatial mapping revealed a striking clustering of missense variants in the helical domain (amino acid positions 179–199), a region essential for calcium-dependent gating of the channel. In contrast, variants associated with autosomal dominant Best disease (ADB) were distributed more broadly, particularly in the N-terminal half of the protein. This divergence underscores distinct functional mechanisms: while ADB variants likely confer gain-of-function effects through altered gating, ARB variants appear to disrupt structural integrity or channel assembly through loss-of-function mechanisms.163222-33-1 manufacturer
Phenotypic variability was evident despite shared genetic etiology.EphB6 Antibody manufacturer Patients exhibited diverse age of onset—ranging from infancy to adulthood—with 10 diagnosed before age 18 (childhood-onset). Visual acuity at presentation varied widely, from near-normal (LogMAR 0.02) to severely impaired (LogMAR 3.00), with no clear correlation between specific genotypes and baseline VA. However, patients with null alleles (n = 15) presented at a younger median age (19 years) compared to non-carriers (29 years), though the difference was not statistically significant. Notably, patients with normal full-field ERGs were significantly younger (mean 10.7 ± 3.9 years) and had better VA (0.18 ± 0.13 LogMAR) than those with abnormal ERGs (p = 0.0004 and p = 0.02, respectively), indicating early preservation of global retinal function.
Imaging findings further highlighted heterogeneity. Subretinal deposits were present in 80.3% of eyes at diagnosis, but their morphology ranged from unifocal to multifocal, with only two patients developing classic vitelliform lesions resembling autosomal dominant Best disease.PMID:34330077 Subretinal fluid persisted in 75% of eyes over time, and intraretinal fluid was observed in over half. Outer retinal layer thickening was seen in nearly half the cohort, possibly reflecting chronic edema or structural disorganization. Macular RPE atrophy developed in 39.2% of eyes at initial visit and increased slightly at follow-up. Focal choroidal excavation (FCE) was detected in eight eyes of five patients, often associated with flat, irregular pigment epithelial detachments and subretinal hyperreflective material—features suggestive of indolent Type 2 neovascularization.
Electrophysiological data confirmed progressive dysfunction. EOG light peak-to-dark trough ratios were severely reduced bilaterally, disproportionate to ERG changes, emphasizing profound RPE failure. Full-field ERG abnormalities emerged predominantly in older patients, with rod system involvement more pronounced than cone pathways. Pattern ERG responses were abnormal in 84% of eyes, yet normal results were preserved in several children, reinforcing early functional resilience. Longitudinal monitoring in two patients over 5–12 years revealed progressive decline in both DA and LA ERG amplitudes, with greater reduction in dark-adapted responses.
This study demonstrates that ARB is not a uniform condition but rather a clinically heterogeneous disorder shaped by variant type, location, and residual protein function. The presence of hypomorphic missense variants may lead to milder, later-onset phenotypes, while null alleles are associated with earlier manifestation. These findings challenge the notion of ARB as a strict null phenotype and suggest a spectrum of functional impairment. They also highlight the importance of individualized prognosis and the need for personalized therapeutic approaches. As gene replacement therapy advances, understanding the genetic underpinnings and phenotypic diversity will be crucial for patient selection, trial design, and predicting treatment response. This comprehensive characterization provides a vital framework for future research and clinical translation in ARB.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com