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.
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All relevant data are included in the manuscript and supplementary material. Additional data are available on request.
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Funding
This study was supported by a Foundation Grant from the Canadian Institutes of Health Research and a Quality of Life Grant from the Canadian Cancer Society Research Institute awarded to YB (Grant numbers 143310 and 705665, respectively). YB was supported by a New Investigator Award from the Canadian Institute of Health Research during the conduct of this study. JLE was funded by the McLaughlin Centre (Grant #MC-2012-13 and #MC-2014-11-1) and CIHR-Champions of Genetics: Building the Next Generation Grant (FRN: 135730).
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JLE and YB conceived and designed the study. ER, MGS, KRZ, MC, RK, SS, CM, IC, KAS, RHM, JLE, and YB contributed to the development of the gene categories and lists. SK and KRZ developed the bioinformatics pipeline. ER, MGS, and KRZ contributed to drafting of the manuscript with critical input from JLE and YB. All authors provided feedback and contributed to the final version of the manuscript.
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This study was approved by the research ethics board (REB) of Mount Sinai Hospital: REB: 12-0222-E.
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Reble, E., Gutierrez Salazar, M., Zakoor, KR. et al. Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings. Hum Genet 140, 493–504 (2021). https://doi.org/10.1007/s00439-020-02220-9
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DOI: https://doi.org/10.1007/s00439-020-02220-9