The Inova Translational Medicine Institute has been exploring the diagnostic use of whole-genome sequencing in newborns with unexplained syndromes in a research setting and plans to transition to a clinical diagnostic test by the end of this year.
Last week, the Falls Church, Va.-based institute, which is part of the Inova Health System, said it has teamed up with Personalis for the data analysis and interpretation of the ongoing research study.
The study, which started about a year ago and focuses on newborns with syndromes that leave Inova's neonatal intensive care unit without a diagnosis, is part of a maternal fetal medicine program at ITMI that consists of two other projects, all involving whole-genome sequencing.
One is a study of preterm birth, initiated in 2011, for which Inova sequenced the genomes of about 1,000 parent-child trios, including children delivered full-term and children born prematurely and admitted to the NICU at Inova Fairfax Hospital. The researchers recently submitted the results to a scientific journal for publication.
The other is a childhood longitudinal cohort study, started in 2012, that plans to enroll a total of 5,000 families pre-birth and has so far consented more than 2,000. The study will follow children until age 18 and has so far generated whole-genome sequence data for more than 5,000 individuals. In addition to WGS data from parent-child trios, it will analyze gene expression, DNA methylation, and microRNA data and correlate those with clinical and phenotypic information. Based on diseases that manifest in childhood, Inova is building disease-centric cohorts within the study group, Joe Vockley, ITMI's CSO and COO, told Clinical Sequencing News. About 10 percent of children develop a disease, such as asthma, obesity, autism, or developmental disorders, within the first two years, he said.
As part of the studies, the researchers have correlated results from whole-genome sequencing of 1,000 babies to their results from the state of Virginia's newborn screening program, an analysis they plan to publish in the near future.
Sequencing for the preterm birth study was conducted by Complete Genomics. For the childhood longitudinal study and the newborn diagnostic study, Inova contracted sequencing to Illumina's non-CLIA whole-genome sequencing service, which generates about 30x coverage. Illumina completes about 250 to 300 genomes per month for Inova, a rate that the institute plans to double. Gene expression, DNA methylation, and microRNA data is generated by Expression Analysis.
For the newborn diagnostic study, which is funded entirely by Inova, the researchers have focused on the 200 or so babies that are admitted to the Inova Fairfax Hospital NICU each year but leave without a diagnosis. "It's our goal to try and enroll as many of those as we can and to do whole-genome sequencing and try to find out what's wrong with them," Vockley explained.
So far, the researchers have enrolled about 80 families – every family they have approached agreed to participate – and sequenced their genomes. For all of the first six cases they have analyzed so far, they were able identify a disease-causing variant and have reported the results back to families and their physicians.
Inova researchers plan to present several case reports at a pediatrics meeting in May and to submit them for publication in the near future. In one case, the diagnosis changed the type of surgery a baby was scheduled for. "Even though you may not be able to cure a genetic disease, the information you have can have an immediate impact on the care," Vockley said.
In contrast to other diagnostic exome or whole-genome sequencing studies, Inova's study participants have not yet gone through a "diagnostic odyssey," having had few other diagnostic tests, and one goal of the study is to show that in this setting the success rate of whole-genome sequencing is high. "In addition to providing the diagnosis for these families, this will be a demonstration of the efficiency of whole-genome sequencing for diagnostics when you don't bias the sample by having performed all the other diagnostic tests beforehand and filtered out the easy ones," Vockley said.
Inova's internal cost for genome sequencing and analysis is currently about $4,500 per individual, which he hopes will come down to between $2,500 and $3,000 in the future as the cost of sequencing declines to about $1,000.
The cost per parent-child trio is usually less than $13,500, though, because the parents' genomes are often just used to verify a mutation found in the child and not extensively analyzed, Vockley said.
For all of its whole-genome sequencing studies, besides looking for disease-causing variants, Inova analyzes the gene list recommended by the American College of Medical Genetics and Genomics for incidental findings, as well as known cancer genes. The researchers also perform an open-ended analysis of all variants, classifying them as ancestral, familial, potential disease causing, or polymorphisms.
However, "because these are research projects, we do not make any promises of returned results or timelines to the participants," Vockley said.
If they find a clinically significant and medically actionable variant, it gets validated in Inova's CLIA lab before being reported to the participant's physician. A board-certified geneticist and a team of genetic counselors are available to meet with the participant and their physician to explain the results.
In collaboration with scientists at Duke University, Inova researchers are exploring how whole-genome sequencing and incidental findings impact patients and families.
Because its in-house bioinformatics team has been overwhelmed with the number of cases, Inova has partnered with Personalis for the whole-genome sequence data analysis of the NICU diagnostic study, which the company provides at cost as part of the collaboration. Vockley said the primary reason for choosing Personalis is the content of the firm's proprietary databases, which "really gives them an edge on others."
That said, on a number of projects, Inova has been working with others on data analysis, including Qiagen's Ingenuity, which he said has "a very nice process as well"; the Institute for Systems Biology; Illumina; and Complete Genomics.
If the sequence analysis does not yield a diagnosis, Inova will also include expression, methylation, and microRNA data and will track "how many babies have needed what type of analysis to be able to come up with a diagnosis," he said.
The entire process of sequencing, data analysis, and interpretation takes about four to six weeks at the moment, which Vockley said is sufficient in most cases. "For a subset of patients I think that the speed is important, but for the majority of patients the speed is really irrelevant."
Around the end of this year, Inova plans to transition from a research protocol to a diagnostic "whole-genome sequencing by prescription" test, Vockley said. "This is a pilot to see how we would implement such a test into a real clinical CLIA laboratory setting."
Inova has not yet decided whether it will run the test internally – it has its own CLIA laboratory with whole-genome sequencing capabilities – or outsource it to another CLIA lab.
At the time of the transition, "we hope to have in place the information necessary for reimbursement," Vockley said, noting that Inova does not plan to bill insurance companies or families "excessively." "If we can get our cost covered, that would be fine," he said.