Inherited retinal diseases (IRD) are a major cause of visual impairment or even legal blindness.
With a prevalence of 1/3,000 in the general population, IRD form an immense impediment for
many people worldwide. The search for DNA variants responsible for IRD has been a tremendous
success over the past 30 years. However, our ability to interpret the functional and clinical
significance of individual variants, especially missense variants, has not kept pace with the ease
with which we find them.
The general aim of this project is to assess the pathogenicity of missense variants of uncertain
significance - so-called VUS - in two large genes, ABCA4 and USH2A, implicated in two frequent
subtypes of inherited blindness. The functional effect of selected VUS will be examined by means
of in vivo disease modeling in Xenopus tropicalis, an excellent animal model for visual impairment.
To this end, we will make use of an innovative, sophisticated genome editing technique in Xenopus
We expect this study will provide insight into the clinical significance of the examined VUS,
ultimately contributing to a more precise molecular diagnosis in individual patients with IRD and
even offering therapeutic perspectives. Finally, the workflow developed here will be of more
general use, as it will be applicable for other disease genes that have a counterpart in Xenopus.