Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes
ABSTRACT 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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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 reservedHuman Mutation 05/2014; 35(5). DOI:10.1002/humu.22536 · 5.05 Impact Factor
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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.Human Mutation 04/2014; 35(4). DOI:10.1002/humu.22525 · 5.05 Impact Factor
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ABSTRACT: After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.European journal of medical genetics 02/2014; 57(4). DOI:10.1016/j.ejmg.2014.02.002 · 1.49 Impact Factor