CLIA-tested genetic variants on commercial SNP arrays: Potential for incidental findings in genome-wide association studies

National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 06/2010; 12(6):355-63. DOI: 10.1097/GIM.0b013e3181e1e2a9
Source: PubMed


Increases in throughput and affordability of genotyping products have led to large sample sizes in genetic studies, increasing the likelihood that incidental genetic findings may occur. We set out to survey potential notifiable variants on arrays used in genome-wide association studies and in direct-to-consumer genetic services.
We used multiple bioinformatics strategies to identify, and map variants tested for genetic disorders in > or = 2 CLIA-approved laboratories (based on the GeneTests database). We subsequently surveyed 18 commercial single nucleotide polymorphism arrays and HapMap for these variants.
Of 1,362 genes tested according to GeneTests, we identified 298 specific targeted mutations measured in more than or equal to two laboratories, encompassing 56 disorders. Only 88 of 298 mutations could be identified as known single nucleotide polymorphisms in genomic databases. We found 18 of 88 single nucleotide polymorphisms present in HapMap or on commercial single nucleotide polymorphism arrays. Homozygotes for rare alleles of some variants were identified in the Framingham Heart Study, an active genome-wide association studies cohort (n = 8,410).
Variants in genes including APOE, F5, HFE, CYP21A2, MEFV, SPINK1, BTD, GALT, and G6PD were found on single nucleotide polymorphism arrays or in the HapMap. Some of these variants may warrant further review to determine their likelihood to trigger incidental findings in the course of genome-wide association studies or direct-to-consumer testing.

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Available from: Christopher J O'Donnell, Jun 09, 2014
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    • "The proportion of these that would meet criteria for disclosure has not previously been considered. Because of the complexities inherent in exposing participants to predictive genetic information discovered outside of the clinical context (Kohane et al. 2006; Meltzer 2006; Wolf et al. 2008a; Johnson et al. 2010) and because of concerns about blurring the lines between research and clinical care (Caulfield et al. 2008), there has been extensive debate about whether it is appropriate to communicate results derived from genetic research to study participants (Fernandez et al. 2003; Bookman et al. 2006; Fernandez and Weijer 2006; MacNeil and Fernandez 2006; Meltzer 2006; Kozanczyn et al. 2007; Wolf et al. 2008a,b; Fabsitz et al. 2010). Several bodies have presented recommendations for the return of individual genetic results to participants, including the "
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    ABSTRACT: There is an emerging consensus that when investigators obtain genomic data from research participants, they may incur an ethical responsibility to inform at-risk individuals about clinically significant variants discovered during the course of their research. With whole-exome sequencing becoming commonplace and the falling costs of full-genome sequencing, there will be an increasingly large number of variants identified in research participants that may be of sufficient clinical relevance to share. An explicit approach to triaging and communicating these results has yet to be developed, and even the magnitude of the task is uncertain. To develop an estimate of the number of variants that might qualify for disclosure, we apply recently published recommendations for the return of results to a defined and representative set of variants and then extrapolate these estimates to genome scale. We find that the total number of variants meeting the threshold for recommended disclosure ranges from 3955-12,579 (3.79%-12.06%, 95% CI) in the most conservative estimate to 6998-17,189 (6.69%-16.48%, 95% CI) in an estimate including variants with variable disease expressivity. Additionally, if the growth rate from the previous 4 yr continues, we estimate that the total number of disease-associated variants will grow 37% over the next 4 yr.
    Full-text · Article · Dec 2011 · Genome Research
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    • "GWAS have led to the discovery of thousands of genetic variants contributing to variability in a range of common diseases including diabetes, cancer, and cardiovascular disease (Johnson et al., 2010; Johnson & O'Donnell, 2009). It has been noted that few, if any, potentially " notifiable " variants reside on arrays used in GWAS (Johnson et al., 2010). However, this conclusion was arrived at using a more stringent set of criteria for determining the notifiability of IGRRs (Bookman et al., 2006), and not the criteria recommended by the more recent NHLBI workshop on the return of IGRRs (Fabsitz et al., 2010). "
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    ABSTRACT: It is unclear how genomic incidental finding (GIF) prospects should be addressed in informed consent processes. An exploratory study on this topic was conducted with 34 purposively sampled Chairs of institutional review boards (IRBs) at centers conducting genome-wide association studies. Most Chairs (96%) reported no knowledge of local IRB requirements regarding GIFs and informed consent. Chairs suggested consent processes should address the prospect of, and study disclosure policy on, GIFs; GIF management and follow-up; potential clinical significance of GIFs; potential risks of GIF disclosure; an opportunity for participants to opt out of GIF disclosure; and duration of the researcher's duty to disclose GIFs. Chairs were concerned about participant disclosure preferences changing over time; inherent limitations in determining the scope and accuracy of claims about GIFs; and making consent processes longer and more complex. IRB Chair and other stakeholder perspectives can help advance informed consent efforts to accommodate GIF prospects.
    Full-text · Article · Dec 2011 · Journal of Empirical Research on Human Research Ethics
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    • "not precisely mapped or represented against the human genome or within the major databases of genetic variation (Johnson et al., 2010). At the same time, the reference human genome sequence which is used in a wide range of informatics tools (e.g. "
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    ABSTRACT: The International Union of Pure and Applied Chemistry (IUPAC) code specified nearly 25 years ago provides a nomenclature for incompletely specified nucleic acids. However, no system currently exists that allows for the informatics representation of the relative abundance at polymorphic nucleic acids (e.g. single nucleotide polymorphisms) in a single specified character, or a string of characters. Here, I propose such an information code as a natural extension to the IUPAC nomenclature code, and present some potential uses and limitations to such a code. The primary anticipated use of this extended nomenclature code is to assist in the representation of the rapidly growing space of information in human genetic variation. Contact: [email protected] /* */ Supplementary information: Supplementary data are available at Bioinformatics online. Published by Oxford University Press 2010. All rights reserved. For Permissions, please email: [email protected] /* */
    Preview · Article · Mar 2010 · Bioinformatics
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