NEW YORK (GenomeWeb) – Sequencing healthy individuals as a way to assess their risk of serious, heritable conditions has been primarily an academic exercise, years away from being implemented broadly. But, as the costs of sequencing continue to decline and sequencing-based tests become more and more accepted in the clinic, the idea of using the technology to do population-based screening is not as far fetched as it once was.
Under a National Human Genome Research Institute ELSI grant, researchers at the University of North Carolina, Chapel Hill are studying the implications of population-based screening for a select number of serious and actionable genetic conditions.
In a commentary published this month in Genetics in Medicine, the group described the key concepts of the study and how they plan to assess its impact. Employing what they described as a systematic evidence review, they plan to assess the impact of a targeted NGS-based screening test on understanding penetrance and prevalence of disease-causing variants in the general population, as well as the psychological, ethical, legal, and economic impacts of broad testing.
"We're looking at this from the lens of should we be doing it and what are all the considerations," said Anya Prince, lead author of the Genetics in Medicine commentary. Prince has a law degree and is also a post-doctoral fellow at UNC's Center for Genomics and Society.
The UNC team is now in its second year of the Gene-Screen project. The group has chosen the genes that it plans to include in its NGS panel and will now run a pilot study on 50 volunteers. In total, Prince said the group plans to screen around 1,000 healthy individuals.
The panel includes 17 genes corresponding to 11 conditions that are both "preventable and serious," Prince said.
Indicative of how even experts' opinions can vary on what constitutes an actionable finding, the UNC gene list differs from the American College of Medical Genetics and Genomics' list of 56 genes that it recommends laboratories should report back to clinicians ordering exome or whole-genome tests.
Prince said that while the group considered the ACMG gene list, it ultimately decided to develop its own list. "Some of ours match, some don't," she said.
The committee that chose the genes included bioethicists, geneticists, genetic counselors, attorneys, and even anthropologists, she said. "If we're pulling a healthy adult without necessarily a family history and telling them they have this condition, we want to make sure we know a lot about the condition and have tangible pieces of information [about the condition] and can take steps to prevent it," she added.
The Gene-Screen list includes genes related to cancer and cardiovascular disease, such as the genes related to sudden cardiac death, heritable forms of breast cancer, and Lynch syndrome.
Even with something like Lynch syndrome, where the genes and the impact — an increased risk of colorectal, stomach, and ovarian cancers — are well known, most testing for these genes have been in individuals who have a family history or have already been diagnosed.
"You have to think about what some of the extra burdens or benefits might be in testing someone that may not know about their risk," Prince said.
The group will first look at existing evidence from testing asymptomatic individuals with a family history to see what has previously been brought up as a concern for those individuals. For instance, she said, the potential of genetic discrimination is something to take into account. Testing a person for Lynch syndrome who already has colorectal cancer and whose employer knows this is different from testing an asymptomatic individual with no record of the disease and no family history.
Initially, the team plans to recruit around 50 individuals for a pilot study. It will recruit them through general practitioners in North Carolina and will also survey people who ultimately decline to participate to get an understanding of what their concerns are. They will then open it up to around 1,000 individuals also recruited from general practitioners in North Carolina.
They will only report back known pathogenic variants. "Variants of unknown significance are really hard to interpret even with a family history," Prince said. Rather, the group will focus on known variants and gaining a better understanding of their penetrance in the general population. "Penetrance is often determined from families that have the disease," she said, so "it will be interesting to see how many people have these [pathogenic] variants but do not actually get the disease."
Prince said that the Gene-Screen study will help generate information and evidence about all the impacts of population-based genetic screening — including the ethical, psychological, and economic impacts. The technology is there, she said, and has the ability to "really affect people's lives" by potentially preventing cancer or sudden cardiac arrest.
In addition, she cited several recent calls for broader screening for certain conditions. For instance, a recent article in the Journal of the American Medical Association by cancer geneticist Mary-Claire King called for broader screening of BRCA1 and BRCA2 mutations. Another study in the Proceedings of the National Academy of Sciences found that many Ashkenazi Jewish women that tested positive for mutations associated with breast and ovarian cancer risk had high rates of the disease even when they did not have a family history.
Prince noted that evidence from limited populations has shown that population screening can be helpful, and said that ultimately screening will be broadened, at least for some conditions. But, she added, the point of the Gene-Screen project is to "make sure we've thought about what we're doing and how we can do this in the best possible way."