Large Numbers of Genetic Variants Considered to be Pathogenic are Common in Asymptomatic Individuals

Massachusetts Institute of Technology, Cambridge, MA
Human Mutation (Impact Factor: 5.14). 09/2013; 34(9). DOI: 10.1002/humu.22375
Source: PubMed


It is now affordable to order clinically interpreted whole genome sequence reports from clinical laboratories. One major component of these reports is derived from the knowledge base of previously identified pathogenic variants, including research articles, locus specific and other databases. While over 150,000 such pathogenic variants have been identified, many of these were originally discovered in small cohort studies of affected individuals, so their applicability to asymptomatic populations is unclear. We analyzed the prevalence of a large set of pathogenic variants from the medical and scientific literature in a large set of asymptomatic individuals (N = 1,092) and found 8.5% of these pathogenic variants in at least one individual. In the average individual in the 1000 Genomes Project, previously identified pathogenic variants occur on average 294 times (σ = 25.5) in homozygous form and 942 times (σ = 68.2) in heterozygous form. We also find that many of these pathogenic variants are frequently occurring: there are 3,744 variants with MAF > = 0.01 (4.6%) and 2,837 variants with MAF > = 0.05 (3.5%). This indicates that many of these variants may be erroneous findings or have lower penetrance than previously expected. This article is protected by copyright. All rights reserved.

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Available from: Christopher A Cassa
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    • "A study on 500 exomes from European and 500 exomes from African-American adults from the National Heart, Lung and Blood Institute (NHLBI) Exome Sequencing project estimated a frequency of 3.4% and 1.2%, respectively, in individuals of European and African descent, of high-penetrance actionable pathogenic or likely pathogenic variants (Dorschner et al. 2013). Furthermore , studies in asymptomatic individuals and analysis of the " 1000 Genomes " project data have indicated that healthy individuals carry many variants that have been classified as pathogenic in mutation databases, raising the issue that such classification is not always accurate (MacArthur et al. 2012;Xue et al. 2012;Cassa et al. 2013). One study has used data from the NHLBI project to question pathogenicity of previously reported X-linked intellectual disability genes (Piton et al. 2013). "
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    ABSTRACT: New sequencing methods capable of rapidly analyzing the genome at increasing resolution have transformed diagnosis of single-gene or oligogenic genetic disorders in pediatric and adult medicine. Targeted tests, consisting of disease-focused multigene panels and diagnostic exome sequencing to interrogate the sequence of the coding regions of nearly all genes, are now clinically offered when there is suspicion for an undiagnosed genetic disorder or cancer in children and adults. Implementation of diagnostic exome and genome sequencing tests on invasively and noninvasively obtained fetal DNA samples for prenatal genetic diagnosis is also being explored. We predict that they will become more widely integrated into prenatal care in the near future. Providers must prepare for the practical, ethical, and societal dilemmas that accompany the capacity to generate and analyze large amounts of genetic information about the fetus during pregnancy. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Preview · Article · Aug 2015 · Cold Spring Harbor Perspectives in Medicine
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    • "Another major source of analytic error is misinterpretation. Recent analyses indicate that disease-causing variants reported in the medical literature and in large-scale databases such as the Human Gene Mutation Database are frequently incorrect, with reported error frequencies of 4%–23% [Bell et al., 2011; Tong et al., 2011; Cassa et al., 2013]. In addition, current in silico tools for predicting variant pathogenicity, such as SIFT and PolyPhen, have less than 80% accuracy [Gray et al., 2012; Sim et al., 2012]. "
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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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    ABSTRACT: Purpose: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants. Methods: Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. Results: We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable. Conclusion: Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.
    Full-text · Article · May 2014 · Genetics in medicine: official journal of the American College of Medical Genetics
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