NEW YORK (GenomeWeb) – Over 1,500 individuals have enrolled in the various National Human Genome Research Institute-sponsored Clinical Sequencing and Exploratory Research programs, which are studying different facets of best practices for implementing genomic medicine.
During a National Advisory Council for Human Genome Research meeting last week that was webcast, James Evans, a clinical professor of genetics and medicine at the University of North Carolina, Chapel Hill, gave an update on the CSER programs. Evans is the PI of one of the CSER programs that is seeking to establish a framework for returning incidental findings from genome sequencing.
The NHGRI originally granted $40 million in December 2011 to fund five CSER projects headed up at the Baylor College of Medicine, Brigham and Women's Hospital, the Children's Hospital of Philadelphia, the University of North Carolina, and the University of Washington. The five projects are studying a range of issues related to clinical sequencing, including how to extract medically relevant information from a patient's genome sequence, how to integrate genomic data with electronic medical records, patient consent, genetic counseling, and return of results.
Last year, the NHGRI awarded additional grants to projects spearheaded at the Kaiser Research Foundation and Seattle Children's Research Institute, the Hudson-Alpha Institute for Biotechnology, and the University of Michigan.
According to Evans, a total of 1,500 individuals have enrolled in the various programs, about two-thirds of which are adults and 1,000 of which have already been sequenced.
For those that enrolled in the cancer exome sequencing studies, about 2 percent of cases have been a "slam dunk," he said, meaning that sequencing has found a mutation with known clinical significance. In around 25 percent of patients, researchers have found a mutation of potential clinical significance.
In around 817 patients that have undergone germline exome sequencing, 29 percent have positive diagnostic findings. Interestingly, the diagnostic yield of exome sequencing is highly variable depending on the reason for sequencing, Evans said. For instance, in patients with a strong family history of cancer, exome sequencing found variants in cancer predisposition genes in very few cases. But, for individuals with hearing loss or retinal disease, exome sequencing frequently identifies the causative mutation.
In addition, he said, a significant portion of individuals have actionable incidental findings. When using the American College of Medical Genetics and Genomics' recommendation for returning incidental findings in 56 clinically actionable genes, around 2.9 percent of patients that have been sequenced harbor such variants. When using a broader list of genes, as many as 5 percent to 6 percent of patients have incidental findings, Evans said.
How to deal with incidental findings is an active focus of CSER, Evans said. "We've got to figure out what we tell people, what we don't tell people, what we look for, what we don't look for, and who pays," he said.
Progress is being made on this front, however.
Evans said that CSER groups helped influence the ACMG to revise its guidelines on returning incidental findings from clinical sequencing to now give patients a choice to not receive such results.
Additionally, in a study published recently that was led by Gail Jarvik's laboratory at the University of Washington, a group of researchers involved in CSER and the eMERGE project issued recommendations for returning results to individuals participating in genome sequencing research studies.
One thing that complicates the issue though, said Evans, is that people often say one thing but act in a different way. For instance, he said, people frequently say they want all results when simply asked. But, if "even minimal real world structures are in place," for instance, requiring the person to make a phone call, that "dramatically decreases the desired return," he said.
Moving forward, the CSER programs still need to address a number of additional challenges, such as how to deal with variants of unknown significance, which Evans said is the "single biggest challenge to the application of genomic medicine."
Accurately calling variants as pathogenic or benign is another hurdle that is critically important to implementing genomic medicine. False positive results subject patients to "unnecessary surgery, years of unnecessary screening, and a premature end to a diagnostic pursuit," Evans said, while false negative results "forgo necessary preventative therapeutic modalities."
Evans added that while most CSER programs focus on exome or whole-genome sequencing, the actual implementation of sequencing in clinical practice may be more targeted and only to specific patients where such testing is likely to yield results.
"In a clinical setting, focused testing is usually optimal," he said. "Broad testing can lead to waste, false positives, downstream harm, and increased costs."