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Utah Genome Project Aims to Sequence Several Thousand Individuals from Variety of Disease Cohorts

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An ambitious undertaking spearheaded by the University of Utah is aiming to sequence the exomes or whole genomes of several thousand individuals from various disease cohorts in order to pinpoint the genetic underpinnings of those diseases.

The project, which was launched about a year ago, is tapping into the university's extensive Utah Population Database, a 7-million-member repository that includes family histories linked with public health and clinical records.

"The Utah Genome Project is the result of two forces coming together," Lynn Jorde, executive director of the project and chair of human genetics at the University of Utah, told Clinical Sequencing News. "One is affordable genome sequencing and the other is our large Utah families. A lot of people are doing sequencing, but few have access to the [database of] large multigenerational families that we have," he said.

Deb Neklason, program director of the project and a research associate professor at the University of Utah's Huntsman Cancer Institute told Clinical Sequencing News that over 300 people have already been sequenced and the ultimate goal is to sequence between two and three thousand individuals.

There are currently around 15 pilot projects across different disease areas, each with between 15 and 100 individuals enrolled, she said. Additionally, the researchers are aiming to sequence about 500 control individuals.

The individual pilot projects cover both rare and common diseases within the areas of cancer, immune diseases, and heart and lung disorders. There is also a spontaneous pre-term birth study and an obesity project, Neklason said.

A scientific advisory board that includes physicians, computational biologists, and geneticists helps to choose which diseases and proposed projects should be included. The board assesses each disease for how much is known about it, the degree of heritability, the extent to which it clusters in families that are part of the database, and also the public health impact, Jorde said. "We want to target diseases where there's a high probability of finding genes with major events," he said.

The first phase of enrollment began in January of this year, Jorde said, and priority was given to projects where DNA samples had already been collected, so that they could get started right away.

Each individual project goes through its own process of consenting the individuals and must obtain institutional review board approval. However, there is also an overarching IRB for the entire project.

Jorde said that there is a process in place for identifying individuals within the database and then contacting the physician who will approach the individual about the project. Historically, Utah has had a high rate of participation in genetic studies. Jorde said that researchers at the university often realize participation rates as high as 90 percent.

The project aims to have long-term impacts on understanding the genetic roots of disease, as well as short-term impacts that may benefit the study participants themselves.

In the case where sequencing identifies a mutation causative for the particular disease, that result can be confirmed in a CLIA environment and returned to the family.

"We've had a lot of experience over the years in doing that and it's really gratifying to be able to give families answers," Neklason said. "For some, there's actually something they can do about it."

As of yet, the researchers are still working out a policy for returning findings that are not related to the specific disease. "There's a lot of debate in the community about returning results that are not in the targeted [disease] area," Neklason said. "We want to figure out the best way to do that."

Jorde said that such a policy could be similar to the guidelines released by the American College of Medical Genetics and Genomics this spring, which recommended returning known pathogenic variants in around 56 genes related to 24 disorders.

"Our thinking is that any communication back should involve actionable findings," he said. "We haven't formally adopted a guideline at this point, but it could well end up being very similar to the ACMG guidelines."

Sequencing is being done on Illumina HiSeq instruments, with a combination of exome and whole-genome sequencing. For the majority of cases, exome sequencing is used, Neklason said, but there are some individuals whose disease justifies whole-genome sequencing, she said, for instance in pediatric cases where there is evidence that the causative variant is in a non-coding region or is a large insertion or deletion.

The majority of the sequencing is done at the University of Utah's core facility, which currently has two HiSeqs, but will likely soon purchase a third, Neklason said. Additionally, some sequencing is done at ARUP and the researchers will likely need to outsource some sequencing as the project scales up.

Sequencing is done in a research setting both because it is currently more cost efficient — Neklason estimated a research exome would cost around $800 while a CLIA-certified exome could be $3,000 to $8,000 — and also because the researchers are often using blood samples that had previously been drawn in a research context. In the case where a result is to be returned to an individual, that individual must have a fresh blood draw within a clinical environment and then a CLIA-certified test for that specific mutation is performed on the fresh blood draw, Neklason said.

However, in some cases, the researchers are able to make use of ARUP's CLIA-certified exome pipeline. The CLIA-certified protocol is typically reserved for very severe pediatric cases, "where they need an answer and one that they can act upon right now," Neklason said.

Additionally, the team is considering developing its own CLIA-certified sequencing pipeline. "This is an evolving discussion," Jorde said.

Despite being early days of the project, there have already been some successes, Neklason said. In three projects, the researchers have identified candidate genes that they are in the process of validating. And one project already published its findings of a new disease-causing gene for common variable immunodeficiency in the American Journal of Human Genetics.

Exome sequencing of a family with common variable immunodeficiency identified germline mutations in NFKB2. The finding will have implications for diagnosis of the disease, Neklason said, since early diagnosis can be critical for preventing some of the infections that occur as a result of the immune disorder. Other genes are known to be involved in the disease, she added, but this gene had never been previously implicated.

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