Resolving the diagnostic odyssey in inherited retinal dystrophies through long-read genome sequencing

Abstract

Background Inherited Retinal Dystrophies (IRDs) are visually disabling monogenic diseases with remarkable genetic and phenotypic heterogeneity. Mutations in more than 300 different genes have been identified as disease causing. Genetic diagnosis of IRDs has been greatly improved thanks to the incorporation of Next Generation Sequencing (NGS) approaches. However, the current IRD molecular diagnosis yield using NGS is approximately 60% and negative cases can be explained by variants that are not usually identified by the widely used short reads-NGS such as structural variants (SVs) or by variants located in uncovered, low complexity, repetitive, highly homologous, or GC-rich regions. Long-read genome sequencing (LR-GS) is an emerging technology that produces 10-20 kb reads and is expected to overcome short-read sequencing limitations in the clinical context, thus improving the diagnostic yield in heterogeneous diseases as IRDs.