Characterization of ARB in twins: in-trans frameshift and deep intronic BEST1 variants

Autosomal recessive bestrophinopathy (ARB) typically results from biallelic BEST1 coding variants; however, the role of non-coding variants remains under-investigated. We report dizygotic twins with classic ARB who each initially appeared to carry only one frameshift mutation, later found to harbor a second deep intronic variant in trans. Complete ophthalmologic examination, diagnostic imaging, and electrophysiological study were performed. Genetic analysis included whole-exome sequencing followed by targeted Sanger sequencing of intronic regions, confirming BEST1 variants in five family members. Ten-year-old dizygotic twins presented with bilateral reduced visual acuity, hyperopia in at least one eye of each twin, multifocal yellow-white flecks, subretinal hyperreflective material with interlaminar splitting, and mild subretinal/intraretinal fluid. Electro-oculography revealed severely reduced Arden ratios, while full-field electroretinogram revealed subnormal rod and cone responses. Genetic testing identified in trans compound heterozygous BEST1 variants, a maternally inherited frameshift c.353_362dup and a paternally inherited deep intronic variant c.867+97G>A. Asymptomatic parents were heterozygous carriers. This is the first report of dizygotic twins with ARB carrying compound heterozygous BEST1 mutations consisting of a frameshift and the deep intronic variant c.867+97G>A inherited in trans.