Semiautomated approach focused on new genomic information results in time and effort- efficient reannotation of negative exome data
Author:
Ferrer Alejandro1, Duffy Patrick1, Olson Rory J.1, Meiners Michael A.1, Schultz-Rogers Laura2, Macke Erica L.1, Safgren Stephanie1, Morales-Rosado Joel A.3, Cousin Margot1, Oliver Gavin R.1, Rider David1, Williams Megan1, Pichurin Pavel N.1, Deyle David R.1, Morava Eva1, Gavrilova Ralitza H1, Dhamija Radhika1, Wierenga Klass J.1, Lanpher Brendan C.1, Babovic-Vuksanovic Dusica1, Kaiwar Charu4, Vitek Carolyn R.1, McAllister Tammy M.1, Wick Myra J.1, Schimmenti Lisa A.1, Lazaridis Konstantinos N.1, Vairo Filippo Pinto e1, Klee Eric W.1
Affiliation:
1. Mayo Clinic 2. University of North Carolina at Chapel Hill 3. Vanderbilt University Medical Center 4. Children’s Hospital Colorado
Abstract
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.
Publisher
Research Square Platform LLC
Reference29 articles.
1. AFA, S., H. R and G. P. (2015). "RepeatMasker Open-4.0." from http://www.repeatmasker.org. 2. "Towards precision medicine.";Ashley EA;Nat Rev Genet,2016 3. "TREAT: a bioinformatics tool for variant annotations and visualizations in targeted and exome sequencing data;Asmann YW;Bioinformatics,2012 4. Baker, S. W., J. R. Murrell, A. I. Nesbitt, K. B. Pechter, J. Balciuniene, X. Zhao, Z. Yu, E. H. Denenberg, E. T. DeChene, A. B. Wilkens, E. J. Bhoj, Q. Guan, M. C. Dulik, L. K. Conlin, A. N. Abou Tayoun, M. Luo, C. Wu, K. Cao, M. Sarmady, E. C. Bedoukian, J. Tarpinian, L. Medne, C. M. Skraban, M. A. Deardorff, I. D. Krantz, B. L. Krock and A. B. Santani (2019). "Automated Clinical Exome Reanalysis Reveals Novel Diagnoses." J Mol Diagn 21(1): 38–48.DOI: 10.1016/j.jmoldx.2018.07.008. 5. "ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy;Caporali L;Ann Neurol,2020
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