Exome Sequencing Analysis Identifies Possible Causal Variants in a Brazilian Family with Stargardt Disease

Stargardt disease type 1 (STGD1) is a hereditary eye disease characterized by juvenile macular dystrophy associated with alteration in the Retinal Pigment Epithelium (RPE). It displays a recessive inheritance pattern, most patients being homozygotes or compound heterozygotes for mutations in the autosomal ABCA4 or CNGB3 genes; however, variants in at least four additional genes (ELOVL4, PRPH2, PROM1 and BEST1) have been associated with a dominant form of the disease. Purpose: To identify the causal gene in four sisters of non-affected and non-consanguineous parents with STGD1 by performing whole exome sequencing, integrated with deep phenotype characterization. Methods: We sequenced the exome of two of them and applied an integrative approach for annotating (ANNOVAR and Ion Reporter) and prioritizing (Exomiser v7.2.3) their variants. Furthermore, we screened the family for nine candidate variants in seven cs, using Sanger sequencing. Results: Genetic analysis revealed all four sisters were heterozygotes for two ABCA4 missense variants (rs61751406: C>A, p.A1794D and rs56142141: C>T, p.P1948L), as well as for one RDH11 missense variant (rs80140987: G>A, p.E79K). In addition, only the RDH11 and the rarest ABCA4 p.A1794D variants were predicted as pathogenic. Conclusion: We suggest an additive effect of these variants for causing early-onset STGD1 and propose a possibly digenic autosomal additive inheritance in this family. Thus, our results indicate new possible targets for gene therapy and their identification may improve molecular diagnosis of STGD1.