This effort is making rare disease diagnosis likely to experience another revolution in the next decade. Researchers 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. Helpful as it’s been, however, exome sequencing only resolves 25 percent to 50 percent of undiagnosed cases. “Exome sequencing has really been revealing,” says Robert Kliegman, a neonatologist and rare disease specialist at Children’s Hospital of Wisconsin in Milwaukee. Organizations such as MyGene2 and larger, national organizations, such as the Centers for Mendelian Genomics (CMG) and the Undiagnosed Diseases Network (UDN), are using the approach to help diagnose rare diseases, and to end what clinicians call the “diagnostic odyssey” for hundreds of families every year. These days, clinicians can easily order an exome sequence and analysis, and at a commercial cost of around $700-$5,000 the test has become widely available and is often covered by insurers. Back then, sequencing and analyzing a single exome cost between $70,000 and $80,000 and took months to complete. Just ten years ago, the Whitmores’ story would have been very different. Along with just 30 other patients with GNB1 mutations worldwide, the Whitmores enrolled in a research study describing the mutation’s effects, and a paper reporting the findings is now being prepared for publication. ![]() “This was worth its weight in gold,” says Kate. The Whitmores learned that Scarlett had not inherited the mutation from them, and that the disease will most likely spare her heart and lungs, giving them huge peace of mind. In January 2017, a verdict emerged: Scarlett had a rare mutation in the gene encoding G protein subunit beta 1 (GNB1), a component of a molecular switch protein complex known to regulate some neuronal functions. Researchers at Washington University in Seattle then compared Scarlett’s exome sequence to databases containing thousands of sequences in search of a mutation that could explain her symptoms. Nevertheless, just after Scarlett’s first birthday, the Whitmores sent saliva samples to MyGene2, where scientists sequenced each family member’s exome-the 1.5 percent of the genome that encodes proteins. Kate had heard of this type of sequencing before, but it was nearly impossible for the family to access it in Australia, and Scarlett’s geneticist had recommended against it-the approach is not routine in Australian hospitals, making it more expensive and the data more difficult to interpret. It was just eating me up not knowing what was wrongįinally, Kate came across information about an organization in Seattle, Washington, called MyGene2 that was offering to sequence and analyze the genomes of patients with undiagnosed diseases for about $700 per sample. While Scarlett slept, Kate researched her symptoms, which ranged from visual impairment to hypotonia (muscle weakness), trying desperately to figure out what was causing them in her child. “It was just eating me up not knowing what was wrong with her,” she says. But whenever Scarlett cried, Kate agonized, not knowing if her daughter’s pain resulted from expected things, such as teething, or from her mysterious illness. ![]() The Whitmores focused on early intervention therapies for Scarlett, trying to stay positive and enjoy spending time with their daughter. Months passed, and more tests came back negative.
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