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J Mol Diagn. 2018 Dec 31. pii: S1525-1578(18)30256-3. doi: 10.1016/j.jmoldx.2018.11.004. [Epub ahead of print]

Designing and Implementing NGS Tests for Inherited Disorders - a Practical Framework with Step-by-Step Guidance for Clinical Laboratories.

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Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:
Veritas Genetics, Danvers, Massachusetts.
College of American Pathologists, Northfield, Illinous.
Department of Pathology, Harvard Medical School/Brigham and Women's Hospital, Boston, Massachusetts.
Departments of Pathology & Laboratory Medicine and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
Department of Molecular & Genomic Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Department of Pathology, University of Utah School of Medicine/ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri.
Veritas Genetics, Danvers, Massachusetts; Department of Pathology, Harvard Medical School/Massachusetts General Hospital, Boston, Massachusetts. Electronic address:


Comprehensive next-generation sequencing (NGS) tests are increasingly used as first-line tests in the evaluation of patients with suspected heritable disease. Despite major technical simplifications, these assays still pose significant challenges for molecular testing laboratories. Existing professional guidelines and recommendations provide a framework for laboratories implementing such tests, but in-depth, concrete guidance is generally not provided. Consequently, there is variability in how laboratories interpret and subsequently implement these regulatory frameworks. To address the need for more detailed guidance, the College of American Pathologists with representation from the Association for Molecular Pathologists assembled a working group to create a practical resource for clinical laboratories. This initial work is focused on variant detection in the setting of inherited disease and provides structured worksheets that guide the user through the entire life cycle of an NGS test including design, optimization, validation, and quality management with additional guidance for clinical bioinformatics. This resource is designed to be a living document that is publicly available and will be updated with user and expert feedback as the wet bench and bioinformatic landscapes continue to evolve. It is intended to facilitate the standardization of NGS testing across laboratories and therefore to improve patient care.

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