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The diagnosis of retinal dystrophies can be challenging due to the spectrum of protean phenotypic manifestations. This study employed trio-whole-exome sequencing (trio-WES) to unveil the genetic cause of an inherited retinal disorder in a south Indian family. Proband’s initial ophthalmic examinations was performed in the year 2016. WES was performed on a proband-parent trio to identify causative mutation followed by Sanger validation, segregation analysis, sequence and structure-based computational analysis to assess its pathogenicity. Based on the genetic findings, detailed clinical reassessments were performed in year 2020 for the proband and available family members. WES revealed a novel homozygous  BEST1  mutation c.G310A (p.D104N) in the proband and heterozygous for the parents, indicating autosomal recessive inheritance. Segregation analysis showed heterozygous mutation in maternal grandfather and normal genotype for younger brother and maternal grandmother. Moreover, the structure-based analysis revealed the mutation p.D104N in the cytoplasmic domain, causing structural hindrance by altering hydrogen bonds and destabilizing the BEST1 protein structure. Proband’s clinical assessments were consistent with autosomal recessive bestrophinopathy (ARB) phenotype. Additionally, characteristic absent light rise and decreased light peak-to-dark trough ratio (LP:DT) was observed bilaterally in EOG. Our study demonstrates the utility of WES and clinical re-evaluations in establishing the precise diagnosis of autosomal recessive bestrophinopathy associated with a novel mutation, thus expanding the  BEST1 -related mutation spectrum.

Clinical reassessments and whole-exome sequencing uncover novel BEST1 mutation associated with bestrophinopathy phenotype