Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2013; 93(4):631–640. DOI: 10.1016/j.ajhg.2013.08.006


The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.

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Available from: Robin Bennett, Aug 31, 2015
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    • "Recent analyses of WES data suggest that reportable secondary MAVs will be detected often enough by WES and WGS to warrant detailed discussion of secondary MAVs during the consent process for WES/WGS. A study of 1,000 exomes from the NHBLI Exome Sequencing Project provides evidence that 1.8% of adults have a highly penetrant, pathogenic, or likely pathogenic mutation in one of 114 genes associated with medically actionable, adult-onset conditions [Dorschner et al., 2013]. "
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    ABSTRACT: Our increasing knowledge of how genomic variants affect human health and the falling costs of whole genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, in order to anticipate, diagnose and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions co-exist with the potential risks of uninterpretable results, psychological harm, outmoded counselling models and increased health care costs. Here we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counsellors, and clinicians has designed a “Genome Clinic” research project that addresses multiple challenges in genomic medicine – ranging from development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference and the ethics of consent. This article is protected by copyright. All rights reserved
    Preview · Article · May 2014 · Human Mutation
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    • "There is currently limited evidence and agreement on which variants are clinically actionable and medically relevant (Manolio et al. 2013), and even returning (or not) of incidental findings is an area where there is significant debate (McGuire et al. 2013, Shashi et al. 2013, Wolf et al. 2013). Recent studies have suggested that the rate of incidental findings is likely to be relatively low, around 3.4% in patients of European and 1.2% in patients of African descent (Dorschner et al. 2013). Additionally, other emerging data indicate that over 93% of patients choose to receive secondary incidental findings (Shahmirzadi et al. 2013). "
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    ABSTRACT: Massively parallel sequencing (MPS) has become a powerful tool for the clinical management of patients with applications in diagnosis, guidance of treatment, prediction of drug response, and carrier screening. A considerable challenge for the clinical implementation of these technologies is the management of the vast amount of sequence data generated, in particular the annotation and clinical interpretation of genomic variants. Here, we describe annotation steps that can be automated and common strategies employed for variant prioritization. The definition of best practice standards for variant annotation and prioritization is still ongoing; at present, there is limited consensus regarding an optimal clinical sequencing pipeline. We provide considerations to help define these. For the first time, clinical genetics and genomics is not limited by our ability to sequence, but our ability to clinically interpret and use genomic information in health management. We argue that the development of standardised variant annotation and interpretation approaches and software tools implementing these warrants further support. As we gain a better understanding of the significance of genomic variation through research, patients will be able to benefit from the full scope that these technologies offer. This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2014 · Human Mutation
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    • "For many genetic conditions, sequencing of candidate genes is already common practice, and the interrogation includes rigorous evaluation of novel variants that may have little or no prior exposure in the scientific literature or in available databases. At the same time, WGS may uncover incidental findings not related to the original indication for sequencing [27,28]. In a very different scenario in which the patient is generally healthy and does not have a family history suggestive of a genetic condition, the genome could be sequenced as a part of routine preventive medicine. "
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    ABSTRACT: Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care.Methods/design: This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients' genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes and behaviors of physician and patient participants at multiple time points before and after the disclosure of these results. The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine to evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies.Trial registration: identifier NCT01736566.
    Full-text · Article · Mar 2014 · Trials
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