Avidity sequencing of whole genomes from retinal degeneration pedigrees identifies causal variants

Abstract

Abstract Whole genome sequencing has been an effective tool in the discovery of variants that cause rare disease. In this study, we determined the suitability of a novel avidity sequencing approach for rare disease applications. We built a sample to results workflow, combining the novel sequencing technology with standard library preparation kits, analysis workflows, and interpretation tools. We applied the workflow to ten pedigrees with inherited retinal degeneration (IRD) phenotype. Candidate variants of interest identified through whole genome sequencing were further evaluated using segregation analysis. Mutations in known IRD genes were detected in five of the ten cases. Genes with identified high confidence variants associated with retinal degeneration included PEX6, ABCA4, CERKL, MAK , and RDH12 . Pending confirmatory clinical sequencing, we observed a 50% diagnostic yield, consistent with previously reported outcomes of IRD patient analysis. The study confirms that avidity sequencing is effective in detection of causal mutations when used for whole genome sequencing in rare disease applications.