Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Berg, Jonathan S.; Bernhardt, Barbara A.; Burke, Wylie; Cooper, Gregory M.; Garraway, Levi A.; Garrett, Jeremy R.; Jänne, Pasi A.; Joffe, Steven; Kaufman, David; Parsons, D. Williams; Roberts, J. Scott; Wilfond, Benjamin S.; Amaral, Michelle D.; Amendola, Laura M.; Appelbaum, Paul S.; Aronson, Samuel; Arora, Shubhangi; Azzariti, Danielle R.; Barsh, Greg; Bebin, E. Martina; Biesecker, Barbara B.; Biesecker, Leslie G.; Biswas, Sawona; Blout, Carrie L.; Bowling, Kevin M.; Brothers, Kyle B.; Brown, Brian; Burt, Amber; Byers, Peter H.; Caga-Anan, Charlisse; Calikoglu, Muge G.; Carlson, Sara J.; Chahin, Nizar; Chinnaiyan, Arul M.; Christensen, Kurt D.; Chung, Wendy K.; Cirino, Allison L.; Clayton, Ellen Wright; Conlin, Laura K.; Cooper, Gregory M.; Crosslin, David R.; Davis, James V.; Davis, Kelly Cue; Deardorff, Matthew A.; Devkota, Batsal; Diamond, Pamela M.; Dorschner, Michael O.; Dugan, Noreen P.; Dukhovny, Dmitry; Dulik, Matthew C.; East, Kelly M.; Rivera-Muñoz, Edgar A.; Evans, Barbara J.; Evans, James P.; Everett, Jessica N.; Exe, Nicole; Fan, Zheng; Feuerman, Lindsay Z.; Filipski, Kelly K.; Finnila, Candice R.; Fishler, Kristen; Fullerton, Stephanie M.; Ghrundmeier, Bob; Giles, Karen; Gilmore, Marian J.; Girnary, Zahra S.; Goddard, Katrina A.B.; Gonsalves, Steven; Gordon, Adam S.; Gornick, Michele C.; Grady, William M.; Gray, David E.; Gray, Stacy W.; Green, Robert C.; Greenwood, Robert; Gutierrez, Amanda M.; Han, Paul K. J.; Hart, Ragan; Heagerty, Patrick J.; Henderson, Gail E.; Hensman, Naomi; Hiatt, Susan M.; Himes, Patricia; Hindorff, Lucia A.; Hisama, Fuki M.; Ho, Carolyn Y.; Hoffman‐Andrews, Lily; Holm, Ingrid A.; Hong, Celine; Horike‐Pyne, Martha; Hull, Sara Chandros; Hutter, Carolyn M.; Jamal, Seema M.; Jarvik, Gail P.; Jensen, Brian C.; Joffe, Steven; Johnston, Jennifer J.; Karavite, Dean; Kauffman, Tia L.; Kaufman, Dave; Kelley, Whitley V.; Kim, Jerry H.; Kirby, Christine; Klein, William M. P.; Knoppers, Bartha Maria; Koenig, Barbara A.; Kong, Sek Won; Krantz, Ian D.; Krier, Joel B.; Lamb, Neil E.; Lambert, Michele P.; Le, Lan; Lebo, Matthew; Lee, Alexander; Lee, Kaitlyn B.; Lennon, Niall J.; Leo, Michael C.; Leppig, Kathleen A.; Lewis, Katie; Lewis, Michelle; Lindeman, Neal I.; Lockhart, Nicole C.; Lonigro, Bob; Lose, Edward J.; Lupo, Philip J.; Rodriguez, Laura Lyman; Lynch, Frances L.; Machini, Kalotina; MacRae, Calum A.; Manolio, Teri A.; Marchuk, Daniel S.; Martinez, Josue Natanael; Masino, Aaron J.; McCullough, Laurence B.; McEwen, Jean; McGuire, Amy L.; McLaughlin, Heather; McMullen, Carmit K.; Mieczkowski, Piotr A.; Miller, Jeff F.; Miller, Victoria A.; Mody, Rajen; Mooney, Sean D.; Moore, Elizabeth; Morris, Elissa; Murray, Michael F.; Muzny, Donna M.; Myers, R; Ng, David; Nickerson, Deborah A.; Oliver, Nelly; Ou, Jeffrey; Parsons, Will; Patrick, Donald L.; Pennington, Jeffrey W.; Perry, Denise; Petersen, Gloria M.; Plon, Sharon E.; Porter, Katie; Powell, Bradford C.; Punj, Sumit; Breitkopf, Carmen Radecki; Raesz-Martinez, Robin; Raskind, Wendy H.; Rehm, Heidi L.; Reigar, Dean A.; Reiss, Jacob A.; Rich, Carla A.; Richards, C. Sue; Rini, Christine; Roberts, Scott; Robertson, Peggy D.; Robinson, Dan R.; Robinson, Jill O.; Robinson, Marguerite; Roche, Myra I.; Romasko, Edward J.; Rosenthal, Elisabeth; Salama, Joseph; Scarano, Maria I.; Schneider, Jennifer; Scollon, Sarah; Seidman, Christine E.; Seifert, Bryce A.; Sharp, Richard R.; Shirts, Brian H.; Sholl, Lynette M.; Siddiqui, Javed; Silverman, Elian; Simmons, Shirley; Simons, Janae V.; Skinner, Debra; Spinner, Nancy B.; Stoffel, Elena M.; Strande, Natasha T.; Sunyaev, Shamil; Sybert, Virginia P.; Taber, Jennifer M.; Tabor, Holly K.; Tarczy‐Hornoch, Peter; Taylor, Deanne; Tilley, Christian R.; Tomlinson, Ashley; Trinidad, Susan Brown; Tsai, Ellen; Ubel, Peter A.; Allen, Eliezer M. Van; Vassy, Jason L.; Vats, Pankaj; Veenstra, David L.; Vetter, Victoria L.; Vries, Raymond De; Wagle, Nikhil; Walser, Sarah A.; Walsh, Rebecca; Weck, Karen E.; Werner‐Lin, Allison; Whittle, Jana; Wilfond, B. S.; Wilhelmsen, Kirk C.; Wolf, Susan M.; Wynn, Julia; Yang, Yaping; Young, Carol; Yu, Joon‐Ho; Zikmund‐Fisher, Brian J.

doi:10.1016/j.ajhg.2016.06.002

Cited by 60 publications

(56 citation statements)

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“…24 Whole-exome (patients 10a, 10b, and 11) or genome (patient 12) sequencing was conducted to a median depth of 65X or 30X, respectively. Exome capture was completed using NimbleGen SeqCapEZ Exome version 3.…”

Section: Methodsmentioning

confidence: 99%

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

et al. 2016

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Objective:To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies.Methods:We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR.Results:We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy.Conclusions:Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

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Section: Methodsmentioning

confidence: 99%

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

et al. 2016

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“…While most attention is currently focused on DNA sequencing [42], it should be emphasized that, however valuable and informative our genomic DNA sequences can be, our genomes do not encapsulate all the needed information that determines our health status as not everything is written in our genomes. While the genotype-first approach [43] is attractive, the road from genotype to phenotype is loaded with caveats and uncertainties [44]—consider, for example, factors such as incomplete penetrance, the description of clinically discordant monozygotic twins (as reported, for instance, among carriers of the ∂508 mutation in cystic fibrosis [45]), the fact that a given mutation can result in clinically distinct disease entities (see, for instance, [46–48]) or can lead to variable pleiotropic effects [49], the description of resilient “superheroes” [50, 51], the difficulties of interpreting variants of unknown significance [52] or even of estimating the relative risks of known pathogenic mutations [53], and the missing heritability [54].…”

Section: Big Data and Clinically Useful Knowledgementioning

confidence: 99%

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

2016

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This era of groundbreaking scientific developments in high-resolution, high-throughput technologies is allowing the cost-effective collection and analysis of huge, disparate datasets on individual health. Proper data mining and translation of the vast datasets into clinically actionable knowledge will require the application of clinical bioinformatics. These developments have triggered multiple national initiatives in precision medicine—a data-driven approach centering on the individual. However, clinical implementation of precision medicine poses numerous challenges. Foremost, precision medicine needs to be contrasted with the powerful and widely used practice of evidence-based medicine, which is informed by meta-analyses or group-centered studies from which mean recommendations are derived. This “one size fits all” approach can provide inadequate solutions for outliers. Such outliers, which are far from an oddity as all of us fall into this category for some traits, can be better managed using precision medicine. Here, we argue that it is necessary and possible to bridge between precision medicine and evidence-based medicine. This will require worldwide and responsible data sharing, as well as regularly updated training programs. We also discuss the challenges and opportunities for achieving clinical utility in precision medicine. We project that, through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen-centered healthcare and sustained well-being.

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“…113 Many of the places that have successfully implemented EMR integration with an ancillary genomic system are academic centers with genomic or information technology expertise and have implemented systems for a specific subset of genomic information (such as pharmacogenomics variants), with fewer institutions offering whole genome or exome testing. 108 Several new companies offer these ancillary systems. Some systems organize, annotate, track variants, and generate a report.…”

Section: Integration Into the Medical Care Of Patientsmentioning

confidence: 99%

“…108 Many practical issues need to be solved for this to occur in a widespread manner. Issues include making reports understandable, interfacing genomic results with the electronic medical record (EMR), bioinformatics tools to help categorize variants, handling of incidental findings, and whether and how to offer genetic reevaluation.…”

Section: Integration Into the Medical Care Of Patientsmentioning

confidence: 99%

Review of Clinical Next-Generation Sequencing

Yohe

Thyagarajan

2017

Archives of Pathology &Amp; Laboratory Medicine

307

195

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Context.-Next-generation sequencing (NGS) is a technology being used by many laboratories to test for inherited disorders and tumor mutations. This technology is new for many practicing pathologists, who may not be familiar with the uses, methodology, and limitations of NGS.Objective.-To familiarize pathologists with several aspects of NGS, including current and expanding uses; methodology including wet bench aspects, bioinformatics, and interpretation; validation and proficiency; limitations; and issues related to the integration of NGS data into patient care.Data Sources.-The review is based on peer-reviewed literature and personal experience using NGS in a clinical setting at a major academic center.Conclusions.-The clinical applications of NGS will increase as the technology, bioinformatics, and resources evolve to address the limitations and improve quality of results. The challenge for clinical laboratories is to ensure testing is clinically relevant, cost-effective, and can be integrated into clinical care.( As with any new technology, the use of NGS in the clinical laboratory has evolved and will continue to evolve over time. New applications for the technology continue to be developed, new bioinformatics and wet bench techniques are being developed to address current limitations and improve performance, and new knowledge regarding interpretation of rare variants is being accumulated. This article is an overview of clinical NGS, including recent trends as well as evolution that will likely occur in the near future. The review is based on peer-reviewed literature and personal experience using NGS in a clinical setting at a major academic center. The Molecular Diagnostics Laboratory at

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Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Abstract: In the originally published version of this article, Table 1 unfortunately included c.542G>A instead of c.542G>T. This mutation was correctly notated as c.

Cited by 60 publications

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Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities

Review of Clinical Next-Generation Sequencing

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