Nav: Home

Findings question implications of notifying patients of incidental genetic findings

January 05, 2016

A review of medical records of patients with genetic variations linked with cardiac disorders found that patients often did not have any symptoms or signs of the conditions, questioning the validity of some genetic variations thought to be related to serious disorders, according to a study in the January 5 issue of JAMA.

Sequencing of selected gene sets, whole exomes, and whole genomes is increasingly used for research and clinical care. These approaches also identify incidental findings (also called secondary findings) of potential clinical relevance. Driven by the prospect for preclinical diagnosis and risk factor mitigation, the American College of Medical Genetics and Genomics has supported the return of medically actionable incidental findings and generated a list of genes in which known or predicted pathogenic (pertaining to genetic cause of a disease or condition) variants should be returned to patients who undergo clinical sequencing. These recommendations have been controversial because the frequency of clinical manifestations of these variants and their implications for diagnosis and management are poorly defined. Phenotype (an appearance or characteristic of an individual, which results from the interaction of the person's genetic makeup and his or her environment) data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants, according to background information in the article.

Dan M. Roden, M.D., and Sara Van Driest, M.D., Ph.D., of the Vanderbilt University Medical Center, Nashville, Tenn., and colleagues determined the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. The study included 2,022 individuals recruited for nonantiarrhythmic drug exposure phenotypes for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 U.S. academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes (potentially fatal cardiac conditions), were assessed for potential pathogenicity by 3 laboratories and by comparison with the database ClinVar. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.

Among the 2,022 study participants, a total of 122 rare variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11 percent of the study cohort). Expert laboratory review of these variants designated 42 as potentially pathogenic, and these classifications were discordant across the laboratories. Review of EMR and electrocardiographic (ECG) data revealed no difference in prevalence of arrhythmia diagnoses or ECG phenotypes among participants with the designated variants compared with those without.

After the researchers performed a manual review of EMR data and an ECG review, the majority of participants with a designated variant in either SCN5A or KCNH2 had no identifiable arrhythmia or ECG phenotype. Among patients with designated variants, 35 percent had evidence of any arrhythmia or ECG phenotype.

The authors write that there are several potential explanations for the paucity of clinical manifestations among participants with these variants, including that some participants may have clinically manifest disease that was not documented in the EMR; these variants may have low penetrance or cause subclinical disease except in the setting of additional genetic or environmental influences; this cohort may not represent individuals at risk for the phenotype; and some of these designated variants may confer little or no increased risk for either arrhythmias or ECG abnormalities.

(doi:10.1001/jama.2015.17701; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Establishing the Clinical Validity of Arrhythmia-Related Genetic Variations Using the Electronic Medical Record

"Establishing the clinical validity of genetic variations proposed as biomarkers for important health conditions can be technically challenging, time-consuming, and expensive. The success of precision medicine ultimately depends on the availability of biomarkers in which the clinical community has confidence," writes William Gregory Feero, M.D., Ph.D., of Maine Dartmouth Family Medicine Residency, Fairfield, Maine, and Associate Editor, JAMA, in an accompanying editorial.

"The report by Van Driest et al provides a glimpse of a potential future in which EMR data might be used to define the clinical validity of biomarkers, genetic or otherwise, more rapidly, and at potentially lower cost, than is possible via traditional approaches. However, the study also exposes some shortcomings in the existing ability to meaningfully predict the consequences of at least some genetic variations currently thought to be causally related to serious disorders. For now, caution should be exercised when considering clinical interventions informed by the presence of 'pathogenic' variations in healthy individuals, families, and populations."

(doi:10.1001/jama.2015.17702; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
-end-


The JAMA Network Journals

Related Genes Articles:

How status sticks to genes
Life at the bottom of the social ladder may have long-term health effects that even upward mobility can't undo, according to new research in monkeys.
Symphony of genes
One of the most exciting discoveries in genome research was that the last common ancestor of all multicellular animals already possessed an extremely complex genome.
New genes out of nothing
One key question in evolutionary biology is how novel genes arise and develop.
Good genes
A team of scientists from NAU, Arizona State University, the University of Groningen in the Netherlands, the Center for Coastal Studies in Massachusetts and nine other institutions worldwide to study potential cancer suppression mechanisms in cetaceans, the mammalian group that includes whales, dolphins and porpoises.
How lifestyle affects our genes
In the past decade, knowledge of how lifestyle affects our genes, a research field called epigenetics, has grown exponentially.
Genes that regulate how much we dream
Sleep is known to allow animals to re-energize themselves and consolidate memories.
The genes are not to blame
Individualized dietary recommendations based on genetic information are currently a popular trend.
Timing is everything, to our genes
Salk scientists discover critical gene activity follows a biological clock, affecting diseases of the brain and body.
New genes on 'deteriorating' Y chromosome
Decoding Y chromosomes is difficult even with latest sequencing technologies.
Newly revealed autism-related genes include genes involved in cancer
Researchers in Italy have applied a computational technique that accounts for how genes interact, to find new networks of related genes that may be involved in autism spectrum disorder.
More Genes News and Genes Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.