BEST1 – Autosomal Recessive Bestrophinopathy

Autosomal recessive bestrophinopathy (ARB) is a distinct retinal dystrophy caused by biallelic mutations in BEST1 and is characterized by multifocal subretinal deposits, cystoid macular edema, subretinal fluid, hyperopia, and an absent electro-oculogram light rise in early life. The phenotype overlaps with dominant Best disease but exhibits earlier onset, widespread RPE disturbance and often angle‐closure glaucoma. The inheritance is autosomal recessive, with unaffected heterozygous carriers showing normal fundus appearance but sometimes subclinical EOG abnormalities.

Genetic evidence is robust: ARB has been reported in 62 probands from 63 unrelated families with biallelic [BEST1] variants demonstrating appropriate segregation in consanguineous and nonconsanguineous pedigrees ([PMID:37747403]). Variants include missense, nonsense, splice-site, small indel, and deep-intronic changes. A common Chinese founder deep-intronic variant c.867+97G>A further supports allelic homogeneity in certain populations ([PMID:37747403]).

The variant spectrum is broad: >45 missense changes affecting conserved transmembrane and cytosolic domains, >10 truncating alleles leading to nonsense-mediated decay, canonical splice-site mutations (e.g. c.1100+1G>A), and small in-frame deletions (e.g. c.535_537delAAC (p.Asn179del)). Recurrent alleles such as c.598C>T (p.Arg200Ter) and the deep-intronic c.867+97G>A are reported across independent cohorts.

Functional studies demonstrate loss-of-function as the predominant mechanism. Patch-clamp recordings of ARB-associated missense mutants show markedly reduced chloride conductance and recessive co-expression patterns ([PMID:21330666]). Many mutants fail to traffic to the plasma membrane and are degraded via the proteasome. Nonsense and splice-site mutations elicit transcript reduction by NMD ([PMID:22199244]). iPSC-RPE from ARB patients exhibit impaired photoreceptor outer segment phagocytosis, indicating RPE dysfunction.

Some heterozygous carriers exhibit normal EOG responses and no overt fundus changes, indicating variable expressivity and reduced penetrance of single-allele variants. A subset of dominant BEST1 alleles causes vitelliform macular dystrophy with a distinct phenotype, underscoring genotype–phenotype correlations within the bestrophinopathy continuum.

Integration of genetic and experimental data supports a Strong gene–disease association. Biallelic BEST1 loss-of-function variants reliably predict ARB, guiding molecular diagnosis, genetic counseling, and potential future gene therapy. Key Take-home: BEST1 sequencing is clinically indicated in early-onset multifocal vitelliform retinopathy to confirm ARB and inform management decisions.

References

• Investigative ophthalmology & visual science • 2023 • Comprehensive Genetic Analysis Unraveled the Missing Heritability and a Founder Variant of BEST1 in a Chinese Cohort With Autosomal Recessive Bestrophinopathy. PMID:37747403
• 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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