Analytical and clinical validation of a genome sequencing-based comprehensive rare disease genomic profiling test

Abstract This study evaluates the performance of the RareVision Whole Genome Sequencing (WGS) assay for comprehensive genomic profiling in rare genetic diseases. The analytical validation assessed the assay’s sensitivity and positive predictive values (PPV) for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a sensitivity of 99.4% for SNVs and 98.7% for indels, with PPVs of 99.3% for SNVs and 98.7% for indels. Clinical validation involved benchmarking against established orthogonal methods, demonstrating high concordance in variant detection with reference laboratories. The assay’s reproducibility was confirmed with 100% inter-precision and intra-precision concordance. The RareVision WGS assay provides detailed genomic insights, enhancing the diagnosis and management of rare genetic disorders by offering a comprehensive and accurate genomic profiling tool. Competing Interest Statement S.S., S.F., J.Y.K., J.K.W., J.L., J-A.K., Y.L., B.B-L.O, W.L., S.L., and E.C-S. are employees of Inocras Funding Statement This research was supported and funded by SNUH Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea (FP-2022-00001-004 to S.-Y.L.), along with Inocras Inc. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: In alignment with ethical guidelines, written informed consent for the publication of their data and/or images was obtained from all participants involved in the study. This consent was part of the initial ethical approval process (IRB-H-0905-041-281 and IRB-H-2202-045-1298 ). Additionally, all patient information presented in this publication has been anonymized to protect patient privacy and confidentiality. The study protocol was approved by the Seoul National University Institutional Review Board, ensuring compliance with the ethical standards outlined in the Declaration of Helsinki, and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The patients participating in this study did not consent to the public release of sequencing data. The WGS pipeline and associated algorithms are proprietary to Inocras Inc.