Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data

• DOI: 10.1007/s00439-024-02664-3
• Publication Date: 2024-03-27T19:02:21Z
• Authors: Alejandro Ferrer; Patrick Duffy; Rory J. Olson; Michael A. Meiners; Laura Schultz-Rogers; Erica L. Macke; Stephanie Safgren; Joel A. Morales-R...; Margot A. Cousin; Gavin R. Oliver; David Rider; Megan Williams; Pavel N. Pichurin; David R. Deyle; Eva Morava; Ralitza H. Gavrilova; Radhika Dhamija; Klass J. Wierenga; Brendan C. Lanpher; Dusica Babovic-Vu...; Charu Kaiwar; Carolyn R. Vitek; Tammy M. McAllister; Myra J. Wick; Lisa A. Schimmenti; Konstantinos N. L...; Filippo Pinto e V...; Eric W. Klee
• Keywords: Genomic information; Exome; Human genetics; Genomic Sequencing

Abstract Introduction: Most rare disease patients (75 − 50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genetic databases to enable rapid review of genetic findings. Methods We tested RENEW in an unselected cohort of 1,066 undiagnosed cases from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. Results 5,741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 seconds per variant (32 hours total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. Discussion New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.