Typical best vitelliform dystrophy secondary to biallelic variants in BEST1

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Pathogenic variants in BEST1 cause autosomal dominant or recessive retinal dystrophies.
• Best vitelliform macular dystrophy (BVMD) is typically associated with heterozygous BEST1 variants.
• Autosomal recessive bestrophinopathy (ARB) is linked to biallelic BEST1 variants, presenting a more severe phenotype.

Purpose of the Study:

• To describe three cases with BVMD-like clinical features and autosomal recessive inheritance.
• To investigate the genetic basis of BEST1-related retinal dystrophies with unusual inheritance patterns.

Main Methods:

• Comprehensive ophthalmic examinations including multimodal imaging, electroretinography (ERG, PERG), and electrooculogram (EOG).
• Genetic analysis of probands and family members.
• Segregation testing and fundus examination of relatives.

Main Results:

• Three unrelated cases presented with BVMD phenotype but had biallelic disease-causing BEST1 variants.
• PERG and ERG were normal; EOG was subnormal or normal/borderline.
• Two cases were homozygous for BEST1 missense variant c.139C>T, p.Arg47Cys; one was homozygous for deletion c.536_538delACA, p.Asn179del.

Conclusions:

• Biallelic BEST1 variants can lead to a BVMD phenotype, mimicking heterozygous inheritance.
• Phenotypic presentation may differ between heterozygous and biallelic carriers of the same BEST1 variants.
• Findings have significant implications for genetic counseling and prognostication in BEST1-related retinal disorders.