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Matthew estimated that, without other affected family members to narrow the target, the sequencing would cost at least half a million dollars.
"What I had proposed was theoretically possible," said Matthew. "But it was anguishing to know that while the technology already existed, it was far too expensive to hunt for mutations this way."
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By the numbers
22,000 » Each person’s number of genes, which make up his or her DNA, the genetic blueprint for human life.
More than 3 billion » The number of “base pairs” that determine genetic makeup.
$3,000 » Cost to sequence a family’s exome, 2 percent of each member’s DNA.
$20,000 » What one family in the Duke study that diagnosed Bertrand spent on dead-end diagnostic tests.
$75,661 » Four years of the Mights’ out-of-pocket health expenses.
$3 billion » Cost of the Human Genome Project, begun in 1990 and completed in 2003.
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Help find a cure
To donate to the Bertrand Might Research Fund at Sanford Burnham, go to: http://bit.ly/QbCUDO
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‘Overwhelming evidence’ • Two weeks later, the phone rang.
At Duke’s Center for Human Genome Variation, researcher David Goldstein wanted to test a new idea for diagnosing the undiagnosable.
He would focus on the "exome," a tiny portion of a genome, the 1.5 percent of human DNA that drives protein production. Misfires in protein production are thought to be responsible for most genetic disorders.
Familiar with Bertrand’s case from the transplant attempt, a member of Goldstein’s team asked to include him in a pilot study of 12 children with developmental delays and birth defects thought to be genetic, but with symptoms that defied explanation.
Goldstein wanted the hardest cases he could find, and Bertrand was the first to come to mind.
"We thought if we could succeed 10 percent of the time," Goldstein later explained, "that would be good enough" to show the approach works.
About a month after the study began, Cristina learned she was pregnant.
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Matthew had become convinced that Bertrand’s mutation was new, not inherited, which meant a second child would not be at risk. Cristina, uncertain, worried during the pregnancy about both children. Contemplating having a child who "would enjoy the park and hug me back," she said, felt like a betrayal of Bertrand.
Victoria was born plump and healthy in 2011.
This May, the family flew to North Carolina to hear Duke’s results — a breakthrough.
Goldstein’s team had landed diagnoses for seven of the 12 children, including Bertrand.
The more than 50 percent success rate, Goldstein said, is "overwhelming evidence" of technology’s promise for "all patients who fail to get a diagnosis through traditional testing."
"There are about 50,000 live births a year of children who probably should be analyzed this way," he said, "and that ignores the backlog."
Exome sequencing has its limits, warns Goldstein. "The vast majority of genetic diagnoses we obtain will not lead to a treatment for the patient. ... And in developmental cases, it will be the case where the damage is done before you get a diagnosis."
Here’s what the Mights now know: Matthew and Cristina each have a different mutation in the same gene, NGLY1, and Bertrand had inherited both.
To claim discovery of a new disease, Duke had to find another Bertrand. But they had double-checked their finding by sending blood samples to Hudson Freeze, a glycobiology expert in La Jolla, Calif. Freeze confirmed Bertrand was producing almost no N-glycanase, an enzyme regulated by the NGLY1 gene.
The enzyme plays a lead role in recycling misfolded proteins, which were accumulating in Bertrand’s body. That night in their hotel room, Matthew and Cristina wondered, could replacing the enzyme help him? They emailed Freeze.
At home, a week later, an exultant Matthew wrote about his wife on Mother’s Day.
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