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Adult-onset foveomacular vitelliform dystrophy (AVMD) is an autosomal dominant macular degeneration characterized by yellow subretinal deposits and mild visual disturbance. Initial multi-center screening in 32 unrelated AVMD patients identified four distinct BEST1 variants, including the splice-site mutation c.636+1G>T, in 12.5% of cases ([PMID:10854112]). However, subsequent cohorts of 19 and 24 AVMD probands showed no pathogenic BEST1 changes ([PMID:21269699]; [PMID:32942919]). A single heterozygous missense variant, c.113T>G (p.Ile38Ser), was later reported in a 51-year-old with AVMD, with patch-clamp studies demonstrating a mild reduction in chloride current relative to wild-type bestrophin-1, consistent with a partial loss-of-function mechanism ([PMID:28831140]).
Overall, heterozygous BEST1 mutations have been detected in fewer than ten unrelated AVMD probands without documented segregation, and negative findings in multiple cohorts dispute a major role. Functional assays for p.Ile38Ser support a mild dominant effect but are limited to a single variant. Further familial segregation and replication in diverse populations are needed to clarify BEST1’s contribution to AVMD.
Gene–Disease AssociationLimitedHeterozygous BEST1 variants reported in ~5 unrelated AVMD probands ([PMID:10854112],[PMID:28831140]) with conflicting negative screens and no segregation Genetic EvidenceLimitedRare splice-site and missense BEST1 variants in AVMD without familial co-segregation Functional EvidenceLimitedPatch-clamp of p.Ile38Ser demonstrates mild loss-of-function in vitro ([PMID:28831140]) |