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. 2021 Mar;23(3):498-507.
doi: 10.1038/s41436-020-01005-9. Epub 2020 Nov 4.

Impact of integrated translational research on clinical exome sequencing

Eric W Klee  1   2   3 , Margot A Cousin #  4   5 , Filippo Pinto E Vairo #  5   6 , Joel A Morales-Rosado #  4   5 , Erica L Macke #  4   5 , W Garrett Jenkinson  4   5 , Alejandro Ferrer  4   5 , Laura E Schultz-Rogers  4   5 , Rory J Olson  4   5 , Gavin R Oliver  4   5 , Ashley N Sigafoos  5   7 , Tanya L Schwab  5   7 , Michael T Zimmermann  8 , Raul A Urrutia  9 , Charu Kaiwar  10 , Aditi Gupta  5 , Patrick R Blackburn  5   11 , Nicole J Boczek  5   11 , Carri A Prochnow  5 , Rebecca J Lowy  5 , Lindsay A Mulvihill  5 , Tammy M McAllister  5 , Stacy L Aoudia  5 , Teresa M Kruisselbrink  5 , Lauren B Gunderson  6 , Jennifer L Kemppainen  5   6 , Laura J Fisher  6 , Jessica M Tarnowski  6 , Megan M Hager  12 , Sarah A Kroc  6 , Nicole L Bertsch  6 , Katherine E Agre  6 , Jessica L Jackson  13 , Sarah K Macklin-Mantia  13 , Marine I Murphree  6 , Laura M Rust  6 , Jolene M Summer Bolster  5 , Scott A Beck  5 , Paldeep S Atwal  13   14 , Marissa S Ellingson  11 , Sarah S Barnett  11 , Kristen J Rasmussen  11 , Carrie A Lahner  11 , Zhiyv Niu  6   11 , Linda Hasadsri  11 , Matthew J Ferber  5 , Cherisse A Marcou  11 , Karl J Clark  5   7 , Pavel N Pichurin  5   6 , David R Deyle  5   6 , Eva Morava-Kozicz  5   6 , Ralitza H Gavrilova  5   6 , Radhika Dhamija  10   12 , Klaas J Wierenga  13   14 , Brendan C Lanpher  5   6 , Dusica Babovic-Vuksanovic  5   6 , Gianrico Farrugia  5   15 , Lisa A Schimmenti  5   6 , A Keith Stewart  16 , Konstantinos N Lazaridis  17   18
Affiliations
Free article

Impact of integrated translational research on clinical exome sequencing

Eric W Klee et al. Genet Med. 2021 Mar.
Free article

Erratum in

  • Impact of integrated translational research on clinical exome sequencing.
    Klee EW, Cousin MA, Pinto E Vairo F, Morales-Rosado JA, Macke EL, Jenkinson WG, Ferrer A, Schultz-Rogers LE, Olson RJ, Oliver GR, Sigafoos AN, Schwab TL, Zimmermann MT, Urrutia RA, Kaiwar C, Gupta A, Blackburn PR, Boczek NJ, Prochnow CA, Lowy RJ, Mulvihill LA, McAllister TM, Aoudia SL, Kruisselbrink TM, Gunderson LB, Kemppainen JL, Fisher LJ, Tarnowski JM, Hager MM, Kroc SA, Bertsch NL, Agre KE, Jackson JL, Macklin-Mantia SK, Murphree MI, Rust LM, Summer Bolster JM, Beck SA, Atwal PS, Ellingson MS, Barnett SS, Rasmussen KJ, Lahner CA, Niu Z, Hasadsri L, Ferber MJ, Marcou CA, Clark KJ, Pichurin PN, Deyle DR, Morava-Kozicz E, Gavrilova RH, Dhamija R, Wierenga KJ, Lanpher BC, Babovic-Vuksanovic D, Farrugia G, Schimmenti LA, Stewart AK, Lazaridis KN. Klee EW, et al. Genet Med. 2023 Feb;25(2):100359. doi: 10.1016/j.gim.2022.12.006. Genet Med. 2023. PMID: 36745126 No abstract available.

Abstract

Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

Methods: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses.

Results: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient.

Conclusion: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Keywords: clinical practice; diagnostic odyssey; genomics; undiagnosed disease; variants of uncertain significance.

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