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Genet Med. 2016 Dec;18(12):1258-1268. doi: 10.1038/gim.2016.40. Epub 2016 Apr 28.

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Author information

1
Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA.
2
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
3
Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA.
4
Division of Cardiology, University of North Carolina School of Medicine, McAllister Heart Institute, Chapel Hill, North Carolina, USA.
5
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
6
Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA.
7
Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
8
Office of Disease Prevention, National Institutes of Health, Bethesda, Maryland, USA.
9
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
10
Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
11
American College of Medical Genetics and Genomics, Bethesda, Maryland, USA.

Abstract

PURPOSE:

Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.

METHODS:

We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.

RESULTS:

We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.

CONCLUSION:

The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.

PMID:
27124788
PMCID:
PMC5085884
DOI:
10.1038/gim.2016.40
[Indexed for MEDLINE]
Free PMC Article

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