This is the second in a series of profiles of centers awarded grants this year by the NIH under the Genomic Sequencing and Newborn Screening Disorders research program.
The University of California San Francisco plans to begin a three-part project next year investigating the risks and benefits of using exome sequencing to help diagnose metabolic and immune disorders and discover important pharmacogenomic variants in infants.
The pilot study, funded with $4.5 million over the next five years, is one of four that received a total of $25 million from the National Human Genome Research Institute and National Institute of Child Health and Human Development this month to explore the potential for genome sequencing to improve newborn healthcare.
The project, led by the university's Robert Nussbaum, will be split into three linked studies which the group expects to conduct simultaneously. The first will be a retrospective analysis of dried blood spots from children with metabolic disorders collected by the California Department of Public Health through a routine banking program.
The second project will offer exome analysis to patients recruited through the lab of UCSF's Jennifer Puck for a disorder called Severe Combined Immunodeficiency. And in the third arm of the study, researchers will offer sequencing to parents of newborns at the UCSF Benioff Children’s Hospital to identify pharmacogenomic variants associated with drug metabolism and adverse reactions to medications.
Puck, who will lead the second section of the study told Clinical Sequencing News that a central goal of the pilot project will be to simply make sure that the team can actually get high-quality sequence and analyze it in a meaningful way in the clinical context of screening and treating newborns.
"We thought that one application we should make a high priority for that first goal would be looking at infants who have a non-normal newborn screening test for a metabolic disorder," she said.
"We want to take these exome sequences and compare – how does a look at the genotype stack up to doing mass spectrometry or whatever tests are done currently, to know if our specificity is the same and if the sensitivity is the same or better [with sequencing], as well as whether current methods and a genomic approach might complement each other."
In this first section of the study, the team intends to obtain blood drops previously collected from 1,400 California children who received standard newborn screening and sequence them in the university's genomics core, which currently uses Illumina HiSeqs, to determine the relative accuracy of exome sequencing compared to current screening methods.
As they move forward with this metabolic analysis, the researchers will also conduct two additional studies in which sequencing will be offered to families, and the process of consent, analysis, and return of results will be studied with an eye to how the process affects patients and families in terms of health, social, legal, and other outcomes.
One effort will recruit families from Puck's lab, which treats children with the immune disorder Severe Combined Immunodeficiency. Puck said the group is hoping to recruit about 50 subjects each year in this part of the pilot to see how exome sequencing compares to the current test for SCID, which her lab developed.
The group will track whether exome sequencing offers increased accuracy in indentifying the disorder with a mind to the potential downsides in consenting families to sequencing, including increased cost and the potential for false positives.
The third section of the project will also offer exome sequencing to families, but in this case to parents of newborns at UCSF's Benioff Children’s Hospital, to assess whether a child has known pharmacogenomic variants that affect the metabolism of certain drugs or the potential to develop adverse side effects.
The PGx arm of the study will allow the team to get a sense of how willing parents are to seek information about their children that might only be relevant or useful later in life. Because it is focused on an area of genomics that offers great potential benefit and little potential risk, Puck said, the PGx study is somewhat "low-hanging fruit."
"Its not like it's predicting whether you are going to get Down syndrome or cancer," she said. "These are things where there is a lot of upside and not a lot of downside."
According to Puck, there may be some crossover between the immune disorder group and the PGx group. "We are also looking at ways to unify the different projects," she said. "For example, some of the patients with immune deficiencies end up requiring things like antibiotics that might have different metabolism based on pharmacogenetic differences, so we can try to exploit the connections between the projects to deal with things that might be very useful for our own patients in their clinical management."
For both the immune disorder and the PGx arms of the study, Puck said the group is planning to focus its reporting to patients and families specifically on variants and information related to these targets, and will take steps to make sure that potential incidental findings are kept out of the clinical analysis.
To do that, she said the team is developing a "concentric circle" system for how to analyze exome sequencing data, as well as separating the job of creating variant files from the job of accessing and interpreting them in the context of the specific question each arm of the study is asking.
"With any deep sequencing there is the chance that you might stumble across something, but we've put some very strict limits in terms of how we are going to do our analysis," Puck said.
According to Puck, all three sections of the pilot will probably kick off simultaneously. The group expects samples from the CDPH for the first arm of the study to come in large batches, while recruiting for the other two sections may flow in smaller numbers, which can hopefully be added onto the runs already being done.
Currently, the plan is for the university's genomics core, equipped with HiSeqs, to do the sequencing, but Puck said the team is not necessarily wedded to that plan for the whole length of the project.
"We are also exploring new platforms, and we are open to checking things out, since this is such a fast-moving field," she said.