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Undiagnosed Diseases Network Reports Diagnostic Rates, Impact on Treatment

NEW YORK (GenomeWeb) – Members of the Undiagnosed Diseases Network (UDN) reported today that they have come to clinical diagnoses for more than one-third of individuals who were fully evaluated through the network over the course of 20 months.

As they reported online yesterday in the New England Journal of Medicine, UDN researchers from Stanford University, Harvard Medical School, and other centers also described 31 new syndromes from mid-September 2015 to late May 2017. Over that time period, they accepted 601 of the more than 1,500 difficult-to-diagnose cases referred to the multidisciplinary program and completed evaluations for 382 individuals.

The team reported that it reached clinical diagnoses for 132 of the 382 cases — 35 percent — including 98 cases diagnosed with exome or whole-genome sequence data and 15 cases diagnosed through clinical reviews. More than half of the individuals diagnosed had typical presentations of known syndromes, the group found, while 18 percent had atypical presentations of known syndromes and 23 percent had new syndromes involving known or new disease genes or regions.

Such diagnoses led to treatment changes for 21 percent of individuals. Other newly diagnosed individuals got other changes in care, including more refined follow up testing. Still others got genetic counseling around specific risk variants without treatment or care changes.

"Our findings underscore the impact that establishing a clear diagnosis can have on clinical decision-making for previously undiagnosed patients," first author Kimberly Splinter, a genetic counselor at Harvard Medical School and associate director of research operations at the UDN's coordinating center, said in a statement. "We hope that the results of this analysis will provide a compelling case for adopting some of the network's diagnostic approaches more broadly in an attempt to clarify diagnoses and refine treatment for patients with rare conditions."

Splinter and her colleagues reported that the UDN's evaluations came with a price tag of $15,116, on average. In contrast, the patients' average cost for care before reaching the UDN came in at nearly $198,700 per person. When the researchers focused in on the newly diagnosed patient group, the average pre-UDN care cost was even higher, at $305,428 per person, and the UDN evaluation cost rose to just over $18,900, on average.

The UDN — which initially encompassed seven clinical sites and two sequencing centers organized around a coordinating center — kicked off in 2014 with $43 million in funding from the National Institutes of Health. It has since expanded to include metabolomics and model organism screening centers; a central biorepository to house, catalog, and distribute biological samples collected for the effort; and a publicly accessible web-based portal known as UDN Gateway. Stanford University's Matthew Wheeler, a co-author on the new paper, presented preliminary UDN findings at the American College of Medical Genetics and Genomics annual meeting in 2017.

In a statement on the new UDN paper, Wheeler touched on a notable case involving a patient with lactic acid buildup in the body that reached dangerous levels who had been part of the network for several years. With the help of sequence data, the team detected a homozygous, missense variant in a mitochondrial ATP synthase enzyme gene called ATP5F1D that led to a diagnosis of the patient's mitochondrial disorder and lactic acidosis — a diagnosis supported by subsequent metabolomic and animal model testing.

"We're learning about biology in a way that could help not just one family, but potentially dozens, even hundreds, of families who suffer that same rare condition," corresponding author Euan Ashley, director of Stanford's Clinical Genome Service and its Center for Inherited Cardiovascular Disease, added. "That's the biggest benefit of this network effect — the impact of identifying one patient's disease could end up being global." 

Members of the network have now received almost 2,800 applications and have accepted close to 1,200 of them. Last month, the NIH announced that it had awarded roughly $100 million in grants to the UDN over the coming four years, as UDN phase II expands to five new clinical sites.

"One role of the UDN should be to demonstrate or refute the usefulness of new diagnostic approaches so that the findings can be integrated into the health care system," the study's authors wrote. They noted that "some of the diagnoses described in this study could be made in the community with better financial support for testing and counseling," whereas "other diagnoses were established with the use of additional resources of the UDN."