First time DNA sequencing saved a patient’s life.

Rsearchers and clinicians are now exploring new tools, such as whole-genome sequencing and RNA analysis, developing better techniques to analyze sequence data, and finding ways to get patients with the same diseases connected faster. This effort is making rare disease diagnosis likely to experience another revolution in the next decade.

Exome explosion

About 15 years ago, Kliegman and his colleagues started noticing a huge unmet need at Children’s Hospital of Wisconsin. Families would end up there after years of searching for a diagnosis, and there was no system in place to settle their cases. Then chair of the pediatrics department at the Medical College of Wisconsin (MCW), Children’s Hospital’s academic partner, Kliegman began bringing together specialists to discuss undiagnosed cases in detail. But the team wasn’t galvanized until it came up against the case of Nic Volker, a young boy with severe inflammatory bowel disease. By the time Volker turned four, his intestines were dotted with holes, he’d had a colostomy, and he mainly ate through a feeding tube. The hospital’s gastrointestinal specialist couldn’t make sense of the disease, leaving Volker’s doctors with no options beyond treating his symptoms.

In 2009, at the request of Volker’s pediatrician, a team at MCW sequenced the boy’s exome. The $75,000 bill was covered by funds raised by Howard Jacob, the founding director of MCW’s genetics center, who hadn’t expected to implement exome sequencing there for at least another five years. Analysis of Volker’s genetic data picked up more than 16,000 gene variants, and four months of sifting through those variants revealed that a mutation in X-linked inhibitor of apoptosis protein (XIAP), a gene on the long arm of the X chromosome, was the likely culprit behind his illness.¹ XIAP mutations were already associated with X-linked lymphoproliferative disease, an immunodeficiency disorder that leaves boys unable to fight off Epstein-Barr virus. Because the gene only affects immune cells, a cord blood transplant to replace Volker’s immune cell progenitors was enough to essentially cure him, says Kliegman. The case became nationally renowned as the first time DNA sequencing saved a patient’s life.

That was one of those
eureka moments.

—Robert Kliegman
Children's Hospital of Wisconsin

In a paper describing the research, the Wisconsin team noted that a thorough study of the available medical literature turned up a list of more than 2,000 gene variants that could have been responsible for Volker’s condition on the basis of his symptoms alone, and XIAP wasn’t on it. The boy’s case “was profound for all of the people in the hospital,” says Kliegman. “That was one of those eureka moments.” The experience led to a shift in the mindset of the hospital’s board, and now genetic sequencing is a cornerstone of the center’s diagnostic approach. By 2014, the MCW’s Human and Molecular Genetics Center (now the Genomic Sciences and Precision Medicine Center) was sequencing more than 700 patients per year.