UNC Lineberger researchers are collaborating through the ClinGen consortium – a program launched to evaluate the clinical relevance of genetic variants – to help physicians make predictions about an individual’s risk of disease, develop more accurate clinical trials and design individualized treatments and care for patients.

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Jonathan Berg, MD, PhD

Millions of genetic variants have been discovered in the last 25 years, but interpreting the clinical impact of the differences in a person’s genome remains a major bottleneck in genomic medicine. In a paper published today in The New England Journal of Medicine, a consortium including investigators from the University of North Carolina School of Medicine and UNC Lineberger Comprehensive Cancer Center present ClinGen, a program launched to evaluate the clinical relevance of genetic variants for use in precision medicine and research.

“Sequencing has revealed that there are potentially several million genetic variants per person,” said Jonathan Berg, MD, PhD, a UNC Lineberger member, an assistant professor in the UNC School of Medicine Department of Genetics and this year’s ClinGen steering committee chair. “Right now there is a certain degree to which we can infer what those variants do, but most of them remain really beyond our understanding of how they are affecting human health, if at all. Through ClinGen, we’re working to evaluate the clinical relevance of genes and variants, and to provide a public database so that labs and clinicians will have a resource that they can go to as a way to understand their patients’ genetic testing results.”

Clinicians and researchers hope to use information about genetic variants not only to make predictions about an individual’s risk of disease, but also to develop more accurate clinical trials and better, tailored treatments and care for patients. However, labs and clinicians may interpret the same variant differently.

Part of ClinGen’s mission is to resolve these differences. Members of ClinGen are actively working with laboratories around the world to help them share their data and implement standards developed by the American College of Medical Genetics and Genomics for interpreting genetic variants, with the goal of resolving interpretation differences.

An integral part of the ClinGen project is ClinVar: a database launched in April of 2013 that currently contains more than 170,000 variant submissions from laboratories around the world. The database is publicly accessible, meaning that clinicians and researchers as well as patients can look up information to find out what is known about a specific genetic variant, and the site gets an average of 5,000 hits per day. The collaborators are working to enhance the number and quality of submissions to the ClinVar database, Berg said.

In addition, ClinGen has formed expert working groups to interpret the strength of gene-disease relationships, resolve differences in the interpretation of variants’ clinical significance found in ClinVar, and move variants into the category of “expert panel reviewed” so they can be used more confidently in clinical decision-making. Berg is a co-principal investigator on the grant awarded to UNC and several partners to support the coordination of the clinical domain working groups. He said the groups are looking at variants that could play a role in a range of diseases including pediatric metabolic disorders, cardiovascular conditions and inherited types of cancer.

“UNC’s main role in ClinGen is, in conjunction with several partners, to coordinate the clinical domain working groups to essentially do the work of curating genes and variants,” Berg said.

Another key aspect of the project will be to develop an informatics system to help the researchers review the genetic variants, Berg said. One of the project goals is to develop machine-learning algorithms to improve the interpretation of the variants.

“Our model works a little like Wikipedia: anyone can submit variants and interpretations to the database to rapidly enable shared resources, but that content is later curated by an expert group to standardize quality,” said Heidi Rehm, PhD, associate professor of pathology at Brigham and Women’s Hospital (BWH) and director of the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine. Investigators from Brigham and Women’s Hospital and Partners HealthCare are also involved in the ClinGen consortium.

ClinGen has also set up a patient portal where those who are interested in sharing their genetic data and health information can register. Known as GenomeConnect, the portal connects researchers, clinicians and patients to learn about the effects of genetics on human health and disease. Patients who have had or are considering having genetic testing can share their results and take surveys to share information about their health. De-identified information will be transferred to ClinVar and other ClinGen resources for advancing genomic knowledge and participants will receive updates when there are opportunities to connect with other participants who share the same condition, gene or genetic variant. Patients can access GenomeConnect to join, and ClinVar to search for genetic variants.

ClinGen is funded by the National Human Genome Research Institute, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E). ClinVar is supported by the Intramural Research Program of the NIH, National Library of Medicine.

In addition to Berg, the co-principal investigators of the grant awarded to UNC and its partners include James P. Evans, MD, PhD, the UNC School of Medicine Bryson Distinguished Professor of Genetics and Medicine and a UNC Lineberger member, Michael Watson, PhD, executive director of the American College of Medical Genetics and David Ledbetter, PhD, executive vice president and chief scientific officer of Geisinger Health System.