Absence of Genotype/Phenotype Correlations Requires Molecular Diagnostic to Ascertain Stargardt and Stargardt-Like Swiss Patients

• Main Authors: Virginie M.M. Buhler, Lieselotte Berger, André Schaller, Martin S. Zinkernagel, Sebastian Wolf, Pascal Escher
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Genes
• Subjects: macula dystrophy; retinal degeneration; choroidal dystrophy; Stargardt disease; central areolar choroidal dystrophy; genetic analyses
• Online Access: https://www.mdpi.com/2073-4425/12/6/812

We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic <i>ABCA4</i> variants, c.1760+2T>C and c.4496T>C being novel. The dominantly inherited pathogenic <i>ELOVL4</i> c.810C>G p.(Tyr270*) and <i>PRPH2</i>-c.422A>G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the <i>ELOVL4</i> c.810C>G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the <i>ABCA4</i> and <i>ELOVL4</i> cohorts, the clinical phenotypes of “flecks”, “atrophy”, and “bull”s eye like” were observed by fundus examination. In the small number of patients harboring the pathogenic <i>PRPH2</i> variant, we could observe both “flecks” and “atrophy” clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.