Managing Incidental Findings in Exome Sequencing for Research

Whole genome and exome sequencing (WGS/WES) techniques raise hope for a new scale of diagnosis, prevention, and prediction of genetic conditions, and improved care for children. For these hopes to materialize, extensive genomic research with children will be needed. However, the use of WGS/WES in pediatric research settings raises considerable challenges for families, researchers, and policy development. In particular, the possibility that these techniques will generate genetic findings unrelated to the primary goal of sequencing has stirred intense debate about whether, which, how, and when these secondary or incidental findings (SFs) should be returned to parents and minors. The debate is even more pronounced when the subjects are adolescents, for whom decisions about return of SFs may have particular implications. In this paper, we consider the rise of “genomic citizenship” and the main challenges that arise for these stakeholders: adolescents' involvement in decisions relating to return of genomic SFs, the types of SFs that should be offered, privacy protections, and communication between researchers and adolescents about SFs. We argue that adolescents' involvement in genomic SF-related decisions acknowledges their status as valuable stakeholders without detracting from broader familial interests, and promotes more informed genomic citizens.

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Informed consent for exome sequencing research in families with genetic disease: The emerging issue of incidental findings

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.36706 ◽

2014 ◽

Vol 164 (11) ◽

pp. 2745-2752 ◽

Cited By ~ 27

Author(s):

Amanda L. Bergner ◽

Juli Bollinger ◽

Karen S. Raraigh ◽

Crystal Tichnell ◽

Brittney Murray ◽

...

Keyword(s):

Informed Consent ◽

Exome Sequencing ◽

Genetic Disease ◽

Incidental Findings

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The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience

Genetics in Medicine ◽

10.1038/gim.2014.29 ◽

2014 ◽

Vol 16 (10) ◽

pp. 741-750 ◽

Cited By ~ 37

Author(s):

Lauren Lawrence ◽

Murat Sincan ◽

Thomas Markello ◽

David R. Adams ◽

Fred Gill ◽

...

Keyword(s):

Exome Sequencing ◽

Incidental Findings ◽

Undiagnosed Diseases

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Abstract 12059: Incidental Findings in Cardiomyopathy and Channelopathy Genes Among 5891 Individuals Undergoing Whole-exome Sequencing. What Should be Reported?

Circulation ◽

10.1161/circ.132.suppl_3.12059 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Elisa Mastantuono ◽

Thomas Wieland ◽

Riccardo Berutti ◽

Peter Lichtner ◽

Tim Strom ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Incidental Findings ◽

Genetic Disorders ◽

Molecular Diagnostic ◽

Minor Genes ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Whole Exome ◽

Unknown Significance

Background: Whole-exome-sequencing (WES) is becoming a common molecular diagnostic test for patients with genetic disorders. However, this technique allows the identification not only of mutations responsible for the disease under investigation, but also of variants potentially causing other diseases, the so called “incidental findings” (IFs). The American College of Medical Genetics and Genomics (ACMG) stated that IFs should be reported based on clinical validity and utility and indicated a list of 56 actionable genes. Among these, nearly half (20/56) are major genes associated with channelopathies and cardiomyopathies. Despite these recommendations, most of the studies so far published, reported also mutations in minor genes among the actionable findings. Methods: WES was performed in 5891 individuals without known channelopathies or cardiomyopathies. Exome data were first filtered based on genotype quality. Subsequently, a frequency filter was applied, considering 1000 Genomes, ExAC and our internal exome database. Variants reported as pathogenic in ClinVar or novel but expected to be pathogenic (nonsense, frameshift and splice) were further investigated, following the ACMG guidelines. Major (20) and minor (73) genes associated with channelopathies and cardiomyopathies were evaluated. Results: We identified 3514 variants in the 93 genes under investigation, after applying the quality and frequency filters. Eight variants were classified as pathogenic and 52 as likely pathogenic and they were detected in around 1% of the individuals. The vast majority (85%) of pathogenic or likely pathogenic variants were located in the 20 actionable genes indicated by ACMG. The inclusion of minor genes increased the number of variants of unknown significance (VUS), from 865 to 3454. Conclusion: Our data support the ACMG recommendations in reporting only IFs identified in the 20 major cardiac actionable genes. Indeed, the inclusion of minor genes is mainly increasing the number of VUS, without significantly impacting the number of pathogenic and likely pathogenic variants. The percentage of individuals with potentially clinical relevant variants in these genes is too high in relation to the disease-prevalence: a cardiologic evaluation is warranted.

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Oncologists’ and cancer patients’ views on whole-exome sequencing and incidental findings: results from the CanSeq study

Genetics in Medicine ◽

10.1038/gim.2015.207 ◽

2016 ◽

Vol 18 (10) ◽

pp. 1011-1019 ◽

Cited By ~ 68

Author(s):

Stacy W. Gray ◽

Elyse R. Park ◽

Julie Najita ◽

Yolanda Martins ◽

Lara Traeger ◽

...

Keyword(s):

Exome Sequencing ◽

Cancer Patients ◽

Whole Exome Sequencing ◽

Incidental Findings ◽

Whole Exome

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Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing

Genetics in Medicine ◽

10.1038/gim.2015.5 ◽

2015 ◽

Vol 17 (11) ◽

pp. 939-942 ◽

Cited By ~ 15

Author(s):

Adam A. Nishimura ◽

Brian H. Shirts ◽

Michael O. Dorschner ◽

Laura M. Amendola ◽

Joe W. Smith ◽

...

Keyword(s):

Decision Support ◽

Exome Sequencing ◽

Clinical Decision Support ◽

Incidental Findings ◽

Clinical Decision

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Patients' views on incidental findings from clinical exome sequencing

Applied & Translational Genomics ◽

10.1016/j.atg.2015.02.005 ◽

2015 ◽

Vol 4 ◽

pp. 38-43 ◽

Cited By ~ 56

Author(s):

Kristin E. Clift ◽

Colin M.E. Halverson ◽

Alexander S. Fiksdal ◽

Ashok Kumbamu ◽

Richard R. Sharp ◽

...

Keyword(s):

Exome Sequencing ◽

Incidental Findings ◽

Clinical Exome Sequencing

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Frequency and management of medically actionable incidental findings from genome and exome sequencing data; A systematic review

Physiological Genomics ◽

10.1152/physiolgenomics.00025.2021 ◽

2021 ◽

Author(s):

Amal Elfatih ◽

Idris Mohammed ◽

Doua Abdelrahman ◽

Borbala Mifsud

Keyword(s):

Exome Sequencing ◽

Incidental Findings ◽

Clinical Genetics ◽

Whole Genome ◽

Sequencing Data ◽

Sequencing Technologies ◽

Pathogenic Variants ◽

Sequencing Studies ◽

Different Populations ◽

Genetics And Genomics

The application of whole genome/exome sequencing technologies in clinical genetics and research has resulted in the discovery of incidental findings unrelated to the primary purpose of genetic testing. The American College of Medical Genetics and Genomics published guidelines for reporting pathogenic and likely pathogenic variants that are deemed to be medically actionable, which allowed us to learn about the epidemiology of incidental findings in different populations. However, consensus guidelines for variant reporting and classification are still lacking. We conducted a systematic literature review of incidental findings in whole genome/exome sequencing studies to obtain a comprehensive understanding of variable reporting and classification methods for variants that are deemed to be medically actionable across different populations. The review highlights the elements that demand further consideration or adjustment.

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