Knowledge is Power
There was something different about Cajsa Allen and her son and daughter, now ages 12 and 15. On top of constant battles with pneumonia, sinus infections and other ailments the body ordinarily defeats with ease, the trio showed signs of an autoimmune disorder and adrenal insufficiency, which had caused Allen’s son to suffer hypoglycemic seizures. They had been diagnosed with common variable immunodeficiency (CVID), a rare illness causing dangerously low levels of infection-fighting antibodies. But their particular constellation of symptoms appeared to be a new class of the disease.
The family piqued the interest of the children’s immunologist, Karin Chen, M.D. If she could find the cause of the Allens’ condition, she realized, it could give clinicians a better grasp of CVID. “When I see families like this, where there must be something hereditary going on, I always want to know why,” says Chen. “Because that knowledge allows you to take medicine a step further.” Chen came to the University of Utah for the chance to solve medical genetics mysteries such as this one. As a resident she was inspired by the work of Lynn Jorde, Ph.D., chair of human genetics, on a study that sequenced an entire family for the first time, resulting in identification of a genetic disease – Miller Syndrome. Years later, Chen jumped at the chance to work with Jorde to make similar discoveries.
Genomic sequencing holds huge promise for the estimated 30 million Americans living with an orphan disease, 80 percent of which are inherited. Currently, patients lucky enough to know the cause of their illness have often had to endure an agonizing diagnostic odyssey that lasts years. Even after diagnosis, they face a dearth of treatment options; no FDA-approved drug exists for 95 percent of rare diseases. “‘Rare’ has lost all meaning,” says Allen matter- of-factly. “These illnesses aren’t rare to our family.”
As the Allens’ symptoms suggest, CVID is complex. The “variable” in the name refers to the more than 10 different mutations that have so far been found to trigger the disease, though the genetic causes of 90 percent of CVID cases remain unknown. Chen believed the Allens’ condition was the result of a unique mutation. She thought Karl Voelkerding, M.D., professor of pathology and medical director at University of Utah-owned ARUP, one of seven labs in the country to offer clinical-grade genome sequencing, could help her find it. “We were coming at the question from different angles, but we had a shared motivation in understanding what was going on with the patient,” says Voelkerding. He agreed to put his team, led by bioinformaticist Emily Coonrod, Ph.D., and genetic immunologist Attila Kumánovics, M.D., on the case.
Months later, Kumánovics asked Chen to come to ARUP for a meeting. The excitement in the room was infectious. The night before, he chased down Coonrod and told her excitedly, “We found the gene! We found it!” Kumánovics explained to Chen that they used bioinformatics tools, including the VAAST algorithm developed at the University, to narrow the 22,000 DNA changes found in affected family members down to one candidate. Searching a bank of DNA samples from CVID patients, they found the same mutation in an unrelated man. To their amazement, he had the same unusual presentation of CVID as the Allens. “With these types of studies, the chance that you will find a genetic cause is only 25 to 30 percent,” says Chen. “Our discovery came from a little bit of luck and a lot of hard work.”
Certainty would come only after Chen experimentally proved that the gene was the bona fide cause. This required a different sort of expertise. She contacted Guy Zimmerman, M.D., and Andrew Weyrich, Ph.D., investigators in the University of Utah molecular medicine program who train physician-scientists in translational research. After many late nights spent coaxing secrets from her patients’ cells, Chen found that the mutation prevents a protein from functioning properly, interfering with the body’s ability to fight infection. Now sure of her findings, she shared them with Allen and her husband, who peppered Chen with questions. “That was miraculous,” recalled Allen. “We were medical marvels for a minute instead of just mutations.”
Based on the discovery, ARUP is creating a new diagnostic panel to screen patients for specific CVID-causing mutations so they can receive personalized care. Chen, meanwhile, is further investigating the gene’s role in the immune system, which she hopes will provide insights into how immunodeficiencies develop, one day leading to new treatments. “Finding the cause of a rare disease often teaches us a lot about other diseases,” Jorde told Chen. “It’s like this little window, but it opens up a big room.”
