Using DNA sequencing in medicine: The world starts to figure out how

It’s been more than a decade since the Human Genome Project cracked our genetic code. DNA sequencing is getting cheaper and cheaper. So why isn’t it being used every day in medicine?

The truth is that while we have the technology to blow apart a patient’s DNA and piece it back together, letter by letter, and compare it with normal “reference” DNA, doctors don’t really know what to do with this information. How much of it is really relevant or useful? Should they be giving it back to patients and their families, and how?

Handled badly, the information could do more harm than good. “We don’t want to scare patients for no reason, or for the wrong reason,” says Isaac Kohane, MD, PhD, who chairs the Children’s Hospital Informatics Program.

Seeking a set of best practices for safe, clinically useful genomic sequencing, Boston Children’s Hospital took a crowd-sourcing approach. In January, the hospital launched CLARITY, challenging research groups from around the world to interpret the genomes of three families with unexplained genetic diseases.

Meet the contestants: Several CLARITY teams submitted videos of their own, sharing their vision, methods and approaches.

Forty groups stepped up; of these, 23—representing 10 countries—submitted reports for each of the three families in time for the September 30 deadline.

“We got the best thinking from around the world,” says CLARITY co-organizer David Margulies, MD, executive director of the Gene Partnership at Boston Children’s. “It has moved us toward a consensus on how to report sequencing data for use in the clinic.”

Results are now in. The Division of Clinical Genetics at Brigham and Women’s Hospital, Boston, was named winner, with two strong finalist teams: the University of Iowa and a German team comprised of Genomatix, CeGaT and the University Hospital of Bonn’s Institute of Pathology.

For sixth grader AJ Foye, who suffers from a muscle-weakening condition called centronuclear myopathy, CLARITY solved an 11-year mystery. Eight of the 23 contestants identified alterations in a gene called titin—a gene that encodes part of the contractile structure in muscles.

“Even if we had suspected titin mutations in AJ, it’s an enormous gene, and to sequence it individually, by hand, would have taken nine months in the lab, at a prohibitive cost,” notes CLARITY co-organizer Alan Beggs, PhD, director of the Manton Center for Orphan Disease Research at Boston Children’s.

Beggs plans to model the titin mutation in fast-growing zebrafish, and test panels of drugs that might reverse it—and perhaps help kids like AJ regain their muscle strength. “The finding doesn’t mean we know the treatment now, but it’s pointing us in the right direction,” says AJ’s mother Sarah Foye. “We can cross other possibilities off the list.”

CLARITY also found a likely cause for the second family’s heart rhythm disturbances. Liam Burns, who died 12 days after birth, was found to have mutations in a gene called TRPM4, along with other affected family members. TRPM4 encodes a kind of gate that allows electrical charges in and out of cells—which makes biological sense, since normal muscle function requires a build-up and release of electrical charges. Further research will tell whether TRPM4 defects also explain the family’s structural heart defects and whether drug treatment might be possible.

Genomic medicine—and patients everywhere—are also CLARITY winners. The challenge has accelerated the development of “best practices” for genomic interpretation and return of results, which will be distilled in a scholarly paper to guide practitioners around the world.

“Just by showing that dozens of teams were able to perform this task sends the message that clinical genomics can be practiced now, rather than in 5 years or a decade from now,” says co-organizer Kohane. “The time is now right to do genomic medicine.”

Here’s the complete list of CLARITY’s contestants:

Division of Clinical Genetics at Brigham and Women’s Hospital (Boston, Mass)

Genomatix (Munich, Germany), CeGaT (Tübingen, Germany), Institute of Pathology, University Hospital of Bonn (Bonn, Germany)
University of Iowa (Iowa City, Iowa)

Special Mention
Clinical Institute of Medical Genetics (Ljubljana, Slovenia)
• Science for Life Laboratory (SciLifeLab), Karolinska Institute (Solna, Sweden)
Scripps Genomic Medicine, Scripps Translational Science Institute (San Diego, Calif.)
SimulConsult / Geisinger Health System (Chestnut Hill, Mass. / Danville, Pa.)
The Research Institute at Nationwide Children’s Hospital (Columbus, Ohio)

Children’s Hospital of Eastern Ontario (Ottawa, Canada)
Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR) (Biopolis, Singapore)
Institute for Systems Biology (Seattle, Wash.)
National Institutes of Health (Bethesda, Md.)
Omicia Inc./University of Utah (supported by LocusDev Inc) (Emeryville, Calif.)
Pearlgen (Chapel Hill, N.C.)
Radboud University Nijmegen Medical Center (Nijmegen, Netherlands)
Sanofi (Cambridge, Mass.)
Seven Bridges Genomics (Cambridge, Mass.)
SNPedia (Potomac, Md.)
Strand Life Sciences (Bangalore, India)
Tel Aviv University (Israel)
• The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine (Houston, Tex.)
Universidad de Cantabria (Santander, Spain)
Yale School of Public Health, Division of Biostatistics (New Haven, Conn.)