Likely pathogenic structural variants in genetically unsolved patients with retinitis pigmentosa revealed by long-read sequencing

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in <i>EYS</i>, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in <i>EYS</i> detected in our previous study along with structural variants (SVs) in <i>EYS</i> and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in <i>EYS</i> in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.