Researchers at the Medical College of Wisconsin are taking pioneering steps to make whole-genome sequencing a standard part of diagnostic testing for children with rare inherited disorders not easily diagnosed by traditional methods. The technology has come far in the decade since the $3 billion human genome project was published—so far, in fact, that a health insurer has offered to cover the sequencing in cases where it would be cheaper than conventional genetic testing.
Whole-genome sequencing—reading a patient’s entire DNA code—now costs about the same as sequencing just a few genes through commercial diagnostic tests, says Howard Jacob, director of the college’s Human and Molecular Genetics Center.
Over the last year, whole-genome sequencing has proved its medical worth. Scientists have been able to pinpoint the genetic mutations underlying a number of rare, difficult-to-diagnose diseases, in some cases resulting in life-saving treatments. But despite the medical benefits, these efforts have so far been limited to the research realm.
“Howard wants to make this a routine clinical test,” says Nicholas Schork, director of bioinformatics and biostatistics at the Scripps Translational Science Institute. “He has gone the extra mile to convince regulatory and legal people at his institution that this should be part of the diagnostic.”
The Wisconsin team garnered international attention in December when researchers published their effort to diagnose Nicholas Volker, a six-year-old with a severe form of inflammatory bowel disease that failed to respond to treatment. By the age of three, Nicholas had already undergone 100 surgeries to try to repair his damaged digestive system. He also had symptoms of an immune disorder, and physicians were considering a cord-blood transplant—a transfusion of stem cells from umbilical cord blood, similar to a bone-marrow transplant—to reboot his immune system. But without a definitive diagnosis, they were hesitant to undertake this procedure, which carries a significant risk of death.
Jacob took on Nicholas’s case thanks to a desperate letter from his physician. After sequencing the child’s genome, Jacob’s team identified a mutation on the X chromosome that has been linked to an inherited immune disorder. The mutation is unique, not found in any of the other human—or animal—genomes sequenced to date. With the new diagnosis in hand, doctors performed the cord-blood transplant. Eight months later Nicholas is out of the hospital and doing well.
The Volker case was considered a research project. But Jacob felt strongly that genome sequencing should be part of the ordinary diagnostic arsenal for children with rare inherited disorders. He has spent the last year and a half trying to transform what has been a promising medical technology into a routine diagnostic, with standard procedures and clinically certified tests. Five hundred pages of forms later, “we created a separate infrastructure for doing purely clinical cases,” says Jacob, who presented details of his efforts last week at the Future of Genomic Medicine conference in San Diego, California.
“Sequencing is just a small part of it,” adds Sarah Murray, a director of genetics at the Scripps Translational Research Institute. “There is insurance, billing, ethics.” For example, should scientists reveal genetic mutations that don’t underlie the disease at hand but might put the patient at particular risk for other disorders later in life? (Jacob’s team specifically asks families what they want to know from the genome sequence. They can change their minds at any time.)
The team’s most recent success: an unidentified insurance company has said it will cover sequencing costs in cases where the team can demonstrate that it is likely to be cheaper than the typical string of diagnostics. Children with rare diseases often go through a series of tests each of which search one or a few genes for the mutation causing the disease. Exactly how much the center will bill insurance companies is still up in the air, in part because the cost is dropping so rapidly. The time it takes to analyze a genome, a factor in cost, has dropped from a few months to a few weeks. Jacob says he expects to analyze about 20 genomes this year and 100 next year.
The center focuses on patients with rare single-gene diseases and a unique set of symptoms. And it takes only cases in which the researchers think sequencing will help the patient, rather than those that might be interesting purely for research purposes. The DNA is sent to Illumina, a genomics technology company whose sequencing lab has been clinically certified by the Food and Drug Administration. Patients don’t have to pay for sequencing; what isn’t covered by insurance is paid for with philanthropic funding from the center.
Thus far, the team has analyzed the genomes of five children and has another seven on the docket. In two of the first five, the researchers believe they identified a genetic mutation that helped the physician make choices about the patient’s treatment. In one case, sequencing revealed that the child would not benefit from a liver transplant, thus saving the liver for another recipient.
Scientists now broadly agree that reading the sequence of DNA is the easy part of genome analysis; figuring out what the sequence means is the real challenge. To help automate that portion of the process, the Wisconsin team has developed software that flags mutations of interest and combs genetics databases for their potential meaning. Jacob says the center hasn’t yet decided whether to market this software or make it freely available to the genetics community.