One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation.

Autor: Lincoln SE; Invitae, San Francisco, CA, USA., Hambuch T; Invitae, San Francisco, CA, USA. tina.hambuch@invitae.com., Zook JM; National Institute of Standards and Technology, Gaithersburg, MD, USA., Bristow SL; Invitae, San Francisco, CA, USA., Hatchell K; Invitae, San Francisco, CA, USA., Truty R; Invitae, San Francisco, CA, USA., Kennemer M; Invitae, San Francisco, CA, USA., Shirts BH; Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Fellowes A; Peter MacCallum Cancer Centre, Melbourne, Australia., Chowdhury S; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Klee EW; Mayo Clinic, Rochester, MN, USA., Mahamdallie S; The Institute of Cancer Research, London, UK.; Great Ormond Street Hospital for Children, London, UK., Cleveland MH; National Institute of Standards and Technology, Gaithersburg, MD, USA., Vallone PM; National Institute of Standards and Technology, Gaithersburg, MD, USA., Ding Y; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Seal S; The Institute of Cancer Research, London, UK., DeSilva W; Peter MacCallum Cancer Centre, Melbourne, Australia., Tomson FL; SeraCare Life Sciences, Gaithersburg, MD, USA.; Meso Scale Diagnostics, Gaithersburg, MD, USA., Huang C; SeraCare Life Sciences, Gaithersburg, MD, USA., Garlick RK; SeraCare Life Sciences, Gaithersburg, MD, USA., Rahman N; The Institute of Cancer Research, London, UK., Salit M; National Institute of Standards and Technology, Gaithersburg, MD, USA.; Joint Initiative for Metrology in Biology, Stanford University, Stanford, CA, USA., Kingsmore SF; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Ferber MJ; Mayo Clinic, Rochester, MN, USA., Aradhya S; Invitae, San Francisco, CA, USA., Nussbaum RL; Invitae, San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Sep; Vol. 23 (9), pp. 1673-1680. Date of Electronic Publication: 2021 May 18.
DOI: 10.1038/s41436-021-01187-w
Abstrakt: Purpose: To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions.
Methods: An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients.
Results: In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests.
Conclusion: The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.
(© 2021. The Author(s).)
Databáze: MEDLINE
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