There are thousands of diseases in which a single gene is responsible. If you have a faulty version of the cystic fibrosis gene, you’ll get the disease. But the reason for that faulty gene could be any number of variations in that single gene. Now consider the thousands of diseases – heart conditions, lung ailments, most forms of cancer – in which many genes play roles; for each of those genes there are thousands of possible variations that may or may not be associated with disease.
Doctors need to know about those roles, but the scientific data on many variations are scattered throughout the medical literature and in some cases the data are hard to make sense of.
Enter Jonathan Berg and James Evans, clinical geneticists at the UNC School of Medicine. They received a four-year, $8.4-million grant from the National Institutes of Health to help create a detailed database of all genetic variants thought to be related to human disease.
“The expectation with this grant is that we’ll only begin to scratch the surface of the end goal: to have a freely available, public resource that has clinical annotations of the variants in genes that cause or increase the risk of disease.”
This grant is part of a consortium assembled by the National Human Genome Research Institute, called the “Clinical Genomics Resource” or “ClinGen” that consists of two U01 awards, a U41 award, and the National Center for Biotechnology Information (NCBI).
“The expectation with this grant,” Berg said, “is that we’ll only begin to scratch the surface of the end goal: to have a freely available, public resource that has clinical annotations of the variants in genes that cause or increase the risk of disease.”
Berg and Evans are part of an effort to recruit dozens of researchers, clinicians, and gene-sequencing labs around the country to collect variant data, curate the variants for clinical significance, and develop novel ways to figure out the disease-producing capacity of these variants. Once they have all the right people and computer infrastructure in place, the team will begin to build the data set.
Berg said, “We need to be able to say for each variant: what do we know about it? How many times has it been seen in medical cases and in controls? What do our prediction algorithms say about it? What is its predicted effect on the structure of a protein? Is it in an important functional domain?” The list goes on and on. Answering such questions will help Berg’s team score each variant’s pathogenicity.
The UNC group is also very interested in determining the “actionability” of gene-phenotype pairs. This feature may help patients and physicians decide how to handle a broad array of possible genomic findings. For instance, when a patient undergoes clinical genomic testing for a suspected genetic disorder, a clinical geneticist will expect to find only one or two variants that explain the patient’s diagnosis. But the genomic test will also find many other variants that may or may not be associated with other unrelated health issues. The doctor has to make a decision about what to do with the information, and therefore knowing a variant’s “actionability” would be crucial.
Also, Berg said, “When an organization, such as the American College of Medical Genetics and Genomics or the American Academy of Pediatrics, wants to set guidelines about the types of findings that should be reported to patients, this database would be an unbiased and evidence-based metric they could use.”
Once Berg and his colleagues have evaluated the clinical validity and clinical actionability of each variant, they’ll plug the data into a database, a resource that doctors and patients will be able to access.
Berg’s team will first focus on genes and variants implicated in single-gene diseases. After that, the focus will turn to more complex, multi-gene conditions.
“So far, we know that about a quarter of our genes are related to disease,” Berg said. “But as new information and genes are discovered, we want this database to be a resource that continues to grow when we have new findings.”
Jonathan Berg, MD, PhD, is an assistant professor in the Department of Genetics and James Evans, MD, PhD, is the Bryson Distinguished Professor of Genetics and Medicine, both in the UNC School of Medicine. David Ledbetter, of Geisinger Health System, and Michael Watson, of the American College of Medical Genetics and Genomics, are also co-principal investigators on the grant. Both are members of the UNC Lineberger Comprehensive Cancer Center.
This article was originally published by UNC Health Care on October 15, 2013. To access the original article, click here.