By Julia Karow
This is the first in a series of profiles of centers awarded grants under the NHGRI's new Clinical Sequencing Exploratory Research Project program. In our next issue, we plan to profile Brigham and Women's Hospital.
One of the main tasks of a new pediatric clinical sequencing project at the Children's Hospital of Philadelphia will be to define what kind of information to return to patients, according to one of the principal investigators.
Earlier this month, the National Human Genome Research Institute awarded CHOP a four-year, $2.2 million grant under its Clinical Sequencing Exploratory Research Project program to study how healthcare professionals can use genomic sequence information in a clinical setting. Four other centers — at Baylor College of Medicine, Brigham and Women's Hospital, the University of North Carolina Chapel Hill and the University of Washington — received funding under the same program (CSN 12/6/2011).
CHOP will focus on the use of genome sequencing to diagnose pediatric disorders, which comes with its own issues, according to Nancy Spinner, director of the clinical cytogenomics laboratory at CHOP. She and her husband, Ian Krantz, a professor of pediatrics and a clinical geneticist at CHOP, are co-PIs of the project. For example, genetic changes about adult-onset disorders found in a pediatric patient may have profound consequences for parents or other family members, she said.
For their project, the researchers will focus on four types of hereditary diseases: hearing loss, mitochondrial disorders, sudden cardiac arrest, and intellectual disability. All four are heterogeneous, meaning many different genes may cause them, and for each, additional genes or mutations are suspected to be involved.
For each disease, they plan to enroll a cohort of up to 20 patients — the exact number will depend on the final budget and the cost of sequencing — that will be studied by exome sequencing or, in the case of intellectual disability, by whole-genome sequencing. Spinner's cytogenomics lab currently uses microarrays to look for deletions and duplications in patients with intellectual disability, and the hope is to replace this test with a whole-genome sequencing test in the future that could also look for gene mutations.
Sequencing for the project will be undertaken at CHOP, but the organizers are still evaluating the final sequencing pipelines, Spinner said. The hospital's Center for Applied Genomics is heavily invested in Life Technologies' sequencing platform, having purchased 15 SOLiD sequencers last year (In Sequence 10/12/2010), but more recently, CHOP teamed up with China's BGI to establish a Joint Genome Center at the hospital, known as BGI@CHOP, which will be more focused on Illumina technology (CSN 11/9/2011).
While the sequencing itself may not be performed in a CLIA lab, the entire workflow will be validated in accordance with CAP and CLIA guidelines, Spinner said. It is a model that has worked well for her clinical cytogenomics lab, which during the past three years has had its arrays run in a core facility that is not CLIA-certified. This approach means, for example, that all samples come to the CLIA lab first, and all sequencing reagents used to analyze them are validated for clinical use.
For the project, the researchers will collect samples from both patients and their parents, but for budget reasons, only the patient samples will be sequenced, though parental samples might be used to validate variants.
In the first year, the plan is to study patients in whom the molecular defect is already known in order to validate the process, but in subsequent years, the project plans to sequence patients where the mutation is unknown and not obvious from the phenotype.
The sequencing data will be analyzed by the group of Peter White, director of the Center for Biomedical Informatics at CHOP, which plans to develop bioinformatic analysis tools as well as processes to deliver results into patients' electronic health records. The group will produce a list of variants and use a variety of tools to help determine which of these are likely to be clinically significant, which it will deliver back to a sequence data oversight committee. That group will then correlate the variants with the phenotype, which is not a trivial task, according to Spinner.
"We believe that bioinformatics tools are completely fantastic and allow you to cut through large amounts of data to come down to a smaller group, but they are not perfect," she said. "Certainly our cytogenomics experience has taught us that you really have to go through each thing; we even may have to go back to preliminary data when there is something that doesn't match with the phenotype. There is just so much that we don’t yet understand."
A big part of the project will be to determine what information to return to families, and research led by Barbara Bernhardt, a genetic counselor and clinical professor of medicine at the University of Pennsylvania's Perelman School of Medicine, will support this. Her group will conduct focus groups, interviews, and surveys with parents, patients, and healthcare providers in order to find out what results they prefer to receive, and to evaluate the informed consent process. "Parents need to understand what kinds of information they could get; they need to be clear about what they want to receive back," Spinner said. Results could include, for example, susceptibility to adult-onset diseases such as cancer or Parkinson's. "Actionable results" are among those that many people feel should be returned, according to Spinner.
One of the greatest challenges will be to deal with the uncertainty of many results, and how to communicate them to parents and their families. "We have already seen from cytogenomics that there are many things that confer genetic susceptibility in an unpredictable way," Spinner said, "and as a community, we really have to get comfortable with what information is certain enough to hand out as a diagnostic test."
For example, in some of the genomes sequenced so far, mutations have been found that predict disease, but the disease was absent in those individuals. Also, so-called variants of unknown significance can be confusing for both doctors and patients, and new educational tools need to be developed to explain what they mean. A recent pilot study that will be published soon, for example, showed that families who were informed about a change of unknown significance found this to be confusing and difficult to understand, Spinner said. "I think clinicians right now are very nervous about all of the things we are going to find that we don't understand."
Towards the end of the project, CHOP, which is going to form a consortium with the other four centers funded under the program, expect to propose guidelines on how to share, interpret, and use genome sequence data in the clinic.
Have topics you'd like to see covered in Clinical Sequencing News? Contact the editor at jkarow [at] genomeweb [.] com.