NEW YORK (GenomeWeb) – The National Human Genome Research Institute is planning to expand its Electronic Medical Records and Genomics (eMERGE) project to include the targeted sequencing of around 25,000 individuals in a CLIA-certified setting in order to study health outcomes of individuals with rare variants in medically important genes.
In a meeting this week that was webcast, the National Advisory Council for Human Genome Research cleared phase III of the project, which seeks to understand the health outcomes that are associated with rare variants in around 100 clinically actionable genes.
Requests for applications for the third phase will likely be released in the next few months. Assuming funding is available within NHGRI, grant decisions will likely be made in the spring next year, and the third phase could begin in the summer or fall of 2015,Rongling Li, the program director of eMERGE, told Clinical Sequencing News in an email following the meeting.
During the meeting, Teri Manolio, director of the division of genomic medicine at NHGRI, laid out the concepts and goals behind the next segment of eMERGE.
The third phase aims to support between eight and 12 study sites, a coordinating center, and one or two CLIA-certified sequencing centers. Researchers will sequence between 2,000 and 3,000 samples per study site and the eMERGE steering committee will decide on the type of sequencing to be done. In her presentation, Manolio described a likely scenario of doing a targeted sequencing panel of around 100 genes for which there is data supporting their actionability, however, the request for applications will allow applicants to determine how much sequencing to include.
Manolio said she anticipates that the protocol "could evolve as the technology evolves," but it's especially focused on understanding rare variants in genes that experts have determined are clinically actionable. For instance, she noted that the American College of Medical Genetics and Genomics lists 56 genes that it deems medically actionable and others have more expansive lists, but they include genes related to "hereditary cancer syndromes, some sudden death syndromes, and a variety of other things that are both uncommon, quite serious, and actionable."
The goal is to better understand their frequency and penetrance in the general population. "They were identified in basically selected people who were at high risk," Manolio explained. But to truly understand the impact of the variants, she said it is important to know how often they occur in an unselected population. A few studies have estimated that between 2 percent and 4 percent of the general population carry such variants, she said. Another component of the next phase of eMERGE will be to "develop approaches for dealing" with such findings, she said.
The NHGRI launched eMERGE in 2007 to develop methods and best practices for conducting genomic research in biorepositories linked to electronic medical records, and it originally included five biorepositories linked to EMRs. It was expanded in 2011 to seven clinical sites, and in 2012 two pediatric sites were added. Researchers involved in the eMERGE program also began studying how such data could be implemented clinically and how it would impact patient care, initially looking at five drug-gene interactions.
In 2012 NHGRI expanded eMERGE again, beginning a collaboration with the Pharmacogenetics Research Network to do targeted sequencing of 84 PGx genes in 9,000 patients.
As an illustration of the need for better annotations of rare variants in the general population, Manolio presented data from an initial evaluation of 2,000 individuals screened with the PGRN-seq panel
Looking at just two genes on the panel that are associated with sudden death, SCN5A and KCNH2, researchers found 85 variants with a minor allele frequency less than 1 percent in SCN5A and 43 variants with a minor allele frequency of less than 1 percent in KCNH2.
Three labs were then asked to determine which of those 128 variants were pathogenic or likely pathogenic. One lab called 16 of those variants pathogenic, another said 24 were pathogenic, and the third lab said 17 were pathogenic, but of all those variants, only four overlapped between all three labs, Manolio said.
Next, eMERGE researchers took the 40 variants that at least one laboratory called as pathogenic, and evaluated the medical records of the 48 individuals that were carriers. Five individuals had cardiac conduction defects that "are quite common in the population and not strongly associated with defects in the genes," Manolio said. None had a history of long QT syndrome, which is what the genes are associated with. One patient had one measured abnormal QT interval, but it had occurred at a time when the patient was "metabolically abnormal," which could have "prolonged her QT," Manolio said. In addition, that same variant was called as pathogenic, benign, and as a variant of unknown significance by the three different labs. "So you can see the problem that we're facing in finding these [variants]," Manolio said.
"Variants with presumed detrimental impact on gene function are often found," but "the phenotypic and clinical implications of these in people who are unselected for disease or positive family history are largely unknown," she added. Additionally, screening for such variants in the general population may prove to be a burdensome task. Given that approximately 2 percent of the initial 2,000 individuals screened via the PGRN-seq had potentially pathogenic variants in two genes, "when one gets up to 56 genes, nearly everybody is going to have something if you don't have some way of culling those down," she added.
One way in which eMERGE could contribute to the better understanding of rare, potentially pathogenic variants is by continuing to develop better electronic phenotyping. As such, Manolio added that another goal of the third phase of eMERGE will be to expand the phenotyping library from 41 to between 60 and 80.
The project will also continue its previous aims of developing clinical decision support tools and enable the integration of genomic information into electronic medical records.
In addition, she said that eMERGE is poised to get "EMR vendors to really engage in genomics." The project has much to "offer in the interface with EMRs." Currently, information is being collected "in haphazard and sporadic ways," Manolio said. "But with EMRs and especially if vendors are engaged, there are tremendous opportunities" to associate phenotype data with genotypes and to better understand "things that remain of fundamental mystery, like penetrance of even well-studied genes."