Sifting DNA Databases for the Right Diagnosis

Genetic analysts can now more quickly identify rare illnesses.

Jackie Smith

Jackie Smith

Source: Claritas Genomics

In 1982, doctors told Jackie Smith’s parents to take the 3-year-old girl home and enjoy her while they could. Her rare muscle disease, likely passed on from a mutation in her parents’ DNA, would probably kill her before she was old enough to drive, they said. Smith, now 35, has lived in the shadow of that diagnosis her whole life, as a small army of physicians failed to diagnose what accounts for her weak limbs and turned-in ankles. This past February, Claritas Genomics gave her the answer in less than three weeks.

Although analysts can quickly sequence a person’s DNA for about $1,000, doctors don’t necessarily know what to look for in those gigabytes of data, because most genetic databases aren’t widely shared or indexed. About 25 million Americans have at least one of 7,000 Mendelian disorders—ailments caused by a defect in a single gene—and researchers have so far matched fewer than half with genetic culprits. Claritas is working to fill in the gaps by isolating specific genes and comparing them against databases of hundreds of thousands of people’s DNA compiled by analytics company WuXi NextCode.

In Smith’s case, Claritas drew up a list of genes that affect children’s nervous systems, then used NextCode’s system to compare her DNA to that of thousands of other people to find similar afflictions. The company identified her condition as centronuclear myopathy, a milder form of the disorder doctors diagnosed back in the ’80s. While there isn’t yet a cure, Smith is participating in research that may one day lead to treatments or more supportive care. “Just being connected feels good. I felt alone for a long time,” she says. “And I want to do it for the bigger picture, too. Not just for myself, but so I can be counted.”

Using a conventional approach, it can take a dozen years and several bad calls by as many doctors to pinpoint these kinds of mutations, says Patrice Milos, chief executive officer of two-year-old Claritas. “The analysis and interpretation have become the bottleneck in diagnosis now that sequencing is the easy part,” says Jeff Gulcher, chief scientific officer at NextCode, an offshoot of Amgen’s DeCode Genetics now owned by WuXi PharmaTech in Shanghai. DeCode got its start in the mid-1990s, collecting DNA data from much of Iceland.

Only a few organizations, including Claritas and a group at Baylor College of Medicine, are making use of large genetic data sets such as NextCode’s as diagnostic tools. Absent that wider lens, many people searching for diagnoses of rare diseases eventually give up, says Anne Rutkowski, director of the Congenital Muscle Disease International Registry. “Getting a diagnosis quickly is critical,” she says. “It’s life-changing for families with young children.”

DNA sequencing and analysis needs to be better standardized to make it more reliable, says Dusica Babovic-Vuksanovic, chair of medical genetics at the Mayo Clinic. Part of that process, she says, involves getting more organizations to build or join larger databases. Another part is keeping eager doctors from making promises they can’t keep. “The tests are fairly complicated and very new,” she says. “Someone who understands what these tests can and cannot do should be involved.”

Genomic diagnosis proved a heartbreaking answer for Linda and Virgil Bennett, who searched for more than two decades to explain why their adopted son Dustin would tremble and violently jerk for hours or days at a time. After dozens of doctor visits and incorrect diagnoses—seizures, muscle disorders, mental health problems—a Mayo Clinic analysis showed he has episodic ataxia type I, a neurological disease characterized by hours-long attacks with no clear trigger. Dustin, a 24-year-old who functions at a first-grade level, is now on the second round of a medication doctors say should help reduce the frequency and severity of his episodes.

“This medicine seems to have relaxed him some,” says Linda Bennett. Dustin is now better able to help his father around the house. It’s tough knowing there isn’t an easy fix just under their noses, she says, but as with Jackie Smith, it’s some relief to have a clear answer. “Now we’re not trying to figure out what it is,” she says, “not trying to keep up with the anxiety of can this get better and can we help any more.”

The bottom line: A big-data approach to genomics is helping diagnose rare illnesses, though treatments for some remain limited.

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