A pathogenic in-frame deletion-insertion variant in BEST1 phenocopies Stargardt disease

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Stargardt disease and Best disease are inherited retinal dystrophies.
• BEST1 gene mutations are known to cause Best disease, a form of macular degeneration.
• Phenotypic variability in inherited retinal diseases can complicate diagnosis.

Purpose of the Study:

• To investigate the genetic cause of a Stargardt disease-like phenotype in a family.
• To characterize the functional impact of a novel BEST1 variant.
• To broaden the understanding of the clinical spectrum of BEST1-associated retinopathy.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• Chloride channel recording in HEK293 cells to assess variant pathogenicity.
• Clinical examinations including funduscopy, electroretinography, and electrooculography.
• Whole-cell patch-clamp recordings to measure chloride conductance.

Main Results:

• A novel 2-base pair deletion insertion in BEST1 (c.1014_1015delGAinsCT) was identified in affected family members.
• The BEST1 variant resulted in a Stargardt disease-like phenotype with varying severity.
• Functional studies confirmed a significant decrease in chloride conductance associated with the mutant BEST1 protein.
• Clinical findings ranged from hyperautofluorescent flecks to advanced retinal pigment epithelium loss.

Conclusions:

• A novel BEST1 genotype can phenocopy Stargardt disease, expanding the known clinical spectrum of BEST1-associated retinopathy.
• The identified BEST1 variant impairs chloride channel function, contributing to the observed retinal phenotype.
• This study highlights the importance of genetic testing in diagnosing atypical presentations of inherited retinal diseases.