Novel BEST1 Variant Characterization in a Large French Cohort in Light of Updated Bestrophin-1 Structure-Function Correlation.

Purpose: To update knowledge on bestrophin-1 structure and function with the aim of assessing the pathogenicity of variants reported in the Leiden Open Variation Database (LOVD) and in a large French cohort of bestrophinopathies.

Methods: All unique variants reported in the latest version (October 2024) of the BEST1-LOVD database were uploaded and curated. We described all BEST1 variants identified in French patients analyzed at Lille University Hospital, between 2008 and 2024. A comprehensive analysis of each variant was performed based on in silico tools (at DNA, RNA, and protein levels), as well as a literature review providing clinical data and functional assays. All of these data were used to classify the variant pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) criteria.

Results: We detailed 488 variants from the LOVD. Among 450 French patients, we identified 150 different variants, 40 of which were novel. We classified only eight variants as variants of unknown significance, four of which were already in the LOVD. We identified specific recurrent variants in the French population: p.(Gly26Asp), p.(Val90Met), p.(Val137Met), and p.(Ile230del), the last of which was present in 17 patients (3.8%). All new variants cause changes in chemical interactions within the protein and are associated with clinical pictures of bestrophinopathy.

Conclusions: The study and comparison of these two large cohorts highlight variants specific to the French population, as well as differences in protein distribution, which are undoubtedly influenced by several population-specific factors. Through multiple in silico analyses, we were able to reclassify 93.3% of variants as likely pathogenic or pathogenic, thereby strengthening clinical diagnoses.