New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease

<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact of<jats:italic>GRK1</jats:italic>missense variants at the protein level were then predicted using a series of computational tools.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all<jats:italic>GRK1</jats:italic>pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We identified new<jats:italic>GRK1</jats:italic>pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1">http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1</jats:ext-link>).</jats:p></jats:sec>