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

Whole genome sequencing has been an effective tool in the discovery of variants that cause rare diseases. 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 this 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 in the additional family members. Potentially causal variants in known IRD genes were detected in five of the ten cases. These high confidence variants were found in ABCA4, CERKL, MAK, PEX6 and RDH12 genes associated with retinal degeneration, that could be sufficient to cause pathology. Pending confirmatory clinical evaluation, 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 variants when used for whole genome sequencing in rare disease applications.

Informations de copyright

Copyright: © 2024 Biswas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Déclaration de conflit d'intérêts

Authors BJK, JM, JZ, BRL, and SK are current or former employees of Element Biosciences, which has commercialized the sequencing technology described in the paper. They may own stock options in the company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Author Contributions PB and RA: study design and manuscript writing. AV, AMB, DL: study design and procuring the DNA and sample information. BJK and JM: preparing libraries and performing sequencing. JZ: study design and library preparation. BRJ and SK: manuscript preparation and analysis.