Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically signif
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ORIGINAL INVESTIGATION
Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings Emma Reble1 · Mariana Gutierrez Salazar1,2 · Kathleen‑Rose Zakoor2 · Sam Khalouei2,3 · Marc Clausen1 · Rita Kodida1 · Salma Shickh1,4 · Chloe Mighton1,4 · Iris Cohn3 · Kasmintan A. Schrader5 · Raymond H. Kim2,3,4,6 · Jordan Lerner‑Ellis2,4,7 · Yvonne Bombard1,4 Received: 16 April 2020 / Accepted: 29 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Genomic sequencing advances have increased the potential to identify secondary findings (SFs). Current guidelines recommend the analysis of 59 medically actionable genes; however, patient preferences indicate interest in learning a broader group of SFs. We aimed to develop an analytical pipeline for the efficient analysis and return of all clinically significant SFs. We developed a pipeline consisting of comprehensive gene lists for five categories of SFs and filtration parameters for prioritization of variants in each category. We applied the pipeline to 42 exomes to assess feasibility and efficiency. Comprehensive lists of clinically significant SF genes were curated for each category: (1) 90 medically actionable genes and 28 pharmacogenomic variants; (2) 17 common disease risk variants; (3) 3166 Mendelian disease genes, (4) 7 early onset neurodegenerative disorder genes; (5) 688 carrier status results. Analysis of 42 exomes using our pipeline resulted in a significant decrease (> 98%) in variants compared to the raw analysis (13,036.56 ± 59.72 raw variants/exome vs 161.32 ± 7.68 filtered variants/exome), and aided in time and costs savings for the overall analysis process. Our pipeline represents a critical step in overcoming the analytic challenge associated with returning all clinically relevant SFs to allow for its routine implementation in clinical practice.
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02220-9) contains supplementary material, which is available to authorized users. * Jordan Lerner‑Ellis Jordan.Lerner‑[email protected] 1
St. Michael’s Hospital, Toronto, ON, Canada
2
Mount Sinai Hospital, Sinai Health System, 700 University Avenue, Toronto, ON M5G 1X5, Canada
3
The Hospital for Sick Children, Toronto, ON, Canada
4
University of Toronto, Toronto, ON, Canada
5
BC Cancer, Vancouver, BC, Canada
6
University Health Network, Toronto, ON, Canada
7
Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
Advances in genomic sequencing technologies, defined here as both exome and genome sequencing, have resulted in decreased sequencing costs and increased diagnostic yield. Studies have found a diagnosis in ~ 42% of pediatric populations compared to 24% from conventional genetic testing (Dillon et al. 2018; Lionel et al. 2018); diagnostic yields in adult populations have ranged from 17 to 25% compared to 11% from panel testing (Posey
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