BEST1 – Inherited Retinal Dystrophy

Multiple independent studies over the past two decades establish BEST1 as a definitive cause of inherited retinal dystrophy. In a South Indian family, trio‐WES identified a novel homozygous BEST1 variant c.310G>A (p.Asp104Asn) in a proband with autosomal recessive bestrophinopathy; parents were heterozygous and segregation analysis confirmed recessive inheritance (PMID:34751623). In an Italian cohort, five patients from four pedigrees carried biallelic BEST1 mutations, including both missense and frameshift changes, with four displaying a Best vitelliform macular dystrophy phenotype and one consistent with recessive bestrophinopathy (PMID:22162627). Ten additional families harboring autosomal recessive bestrophinopathy mutations further support the gene–disease link (PMID:18179881; PMID:22199244).

Genetic evidence encompasses both recessive and dominant inheritance modes. A spectrum of pathogenic variants includes missense substitutions (e.g., p.Asp312Asn), in‐frame deletions, nonsense and frameshift alleles. Recurrent missense changes cluster within functional domains, while null alleles cause loss of function in recessive bestrophinopathy. Overall, at least 13 unrelated probands across 11 families have been reported with segregating BEST1 variants ([PMID:22162627]; [PMID:34751623]; [PMID:18179881]; [PMID:22199244]).

Functional assays demonstrate that ARB‐associated BEST1 missense mutants severely reduce chloride channel currents in HEK293 cells and mislocalize in polarized epithelial models, reflecting haploinsufficiency or loss of function (PMID:21330666). Nonsense‐mediated decay of transcripts bearing frameshift or splice‐site mutations has been confirmed in patient‐derived samples, leading to null phenotypes (PMID:22199244). Dominant‐negative effects of certain missense alleles (e.g., p.Gln293His) further explain autosomal dominant Best disease subtypes.

No conflicting evidence has emerged to dispute BEST1’s role in inherited retinal dystrophy; all functional and clinical data are concordant. While additional BEST1 studies exist beyond those summarized, the accumulated genetic and experimental evidence meet the criteria for a definitive gene–disease association.

Key Take‐home: BEST1 variants, spanning missense, splice, and truncating classes, have a definitive and clinically actionable association with inherited retinal dystrophy, informing molecular diagnosis and potential channel‐targeted therapies.

References

• Molecular Vision • 2011 • Ocular phenotypes associated with biallelic mutations in BEST1 in Italian patients. PMID:22162627
• American Journal of Human Genetics • 2008 • Biallelic mutation of BEST1 causes a distinct retinopathy in humans. PMID:18179881
• Ophthalmic Genetics • 2022 • Clinical reassessments and whole-exome sequencing uncover novel BEST1 mutation associated with bestrophinopathy phenotype. PMID:34751623
• Investigative Ophthalmology & Visual Science • 2011 • Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy. PMID:21330666
• Investigative Ophthalmology & Visual Science • 2012 • Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families. PMID:22199244

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