BEST1 – Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare developmental and degenerative retinal dystrophy characterized by anterior segment anomalies, peripheral concentric retinal hyperpigmentation and eventual vision loss. Variants in BEST1 disrupt the retinal pigment epithelium (RPE) chloride channel bestrophin-1, leading to abnormal ocular patterning and progressive degeneration.

Genetic evidence supports an autosomal dominant inheritance. A heterozygous missense change, c.256G>A (p.Val86Met), was identified in six members of a pedigree with variable anterior segment malformations and segregated with disease in three affected subjects (PMID:21072067). Five additional families harboring heterozygous BEST1 splicing regulator mutations were described, confirming recurrent trans-membrane and splicing-affecting alleles in ADVIRC (PMID:15452077). Overall, more than 12 unrelated probands in ≥6 families have been reported.

The variant spectrum in ADVIRC is dominated by missense substitutions in transmembrane domains and splice sites: recurrent alleles include p.Val86Met, p.Val86Ala, p.Val86Glu and p.Tyr236Cys. Novel variants such as p.Gly83Asp (c.248G>A), p.Ala146Thr (c.436G>A), and a splice-site deletion leading to p.Ser367_Asn579del (c.1101-1T>A) further expand phenotypic heterogeneity (PMID:38957071).

Functional assays indicate that ADVIRC arises from aberrant pre-mRNA splicing and dominant-negative effects. Ex vivo splicing assays showed that exon-skipping mutations c.704T>C (p.Val235Ala) and c.707A>G (p.Tyr236Cys) disrupt exonic splice enhancer binding of ASF/SF2, producing internally deleted bestrophin isoforms (PMID:18611979). Minigene studies of VMD2 splicing regulator mutations confirmed simultaneous missense substitution and in-frame exon skipping in affected individuals (PMID:15452077).

Immunohistochemical analysis of the oldest known ADVIRC patient revealed near absence of bestrophin-1 in the RPE, widespread chorioretinal atrophy with preserved macular island, and RPE migration into the neuroretina, consistent with a primary RPE defect (PMID:29774302). These findings align with chloride channel loss-of-function and abnormal RPE–photoreceptor interactions.

No conflicting evidence disputing the BEST1–ADVIRC association has been reported.

Together, these data indicate a strong gene–disease association for heterozygous BEST1 alleles in ADVIRC, with genetic and functional concordance demonstrating a dominant-negative mechanism through aberrant splicing and channel dysfunction. Genetic testing for BEST1 variants is critical for accurate diagnosis, prognostication, and genetic counselling.

Key Take-home: Heterozygous BEST1 missense and splicing variants cause dominant ADVIRC via aberrant RPE chloride channel function, underpinning personalized diagnostic and therapeutic approaches.

References

• Eye (London, England) • 2011 • BEST1-related autosomal dominant vitreoretinochoroidopathy: a degenerative disease with a range of developmental ocular anomalies. PMID:21072067
• Investigative ophthalmology & visual science • 2004 • Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). PMID:15452077
• Journal of medical genetics • 2009 • ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. PMID:18611979
• Ophthalmic genetics • 2016 • Fundus Autofluorescence and SD-OCT Document Rapid Progression in Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Associated with a c.256G>A Mutation in BEST1. PMID:26771239
• Ophthalmology. Retina • 2018 • Ocular Histopathology and Immunohistochemical Analysis in the Oldest Known Individual with Autosomal Dominant Vitreoretinochoroidopathy. PMID:29774302
• Ophthalmic genetics • 2024 • Variable expressivity of the autosomal dominant vitreoretinochoroidopathy (ADVIRC) phenotype associated with a novel variant in BEST1. PMID:38957071

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