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Genomics Aids NIH Undiagnosed Disease Program

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News – A National Institutes of Health program designed to discover and understand often rare and undiagnosed diseases has identified the genetic cause of a vascular disorder not previously identified in medical literature.

Led by the National Human Genome Research Institute, scientists working in the trans-NIH Undiagnosed Diseases Program (UDP) have found that mutations in one gene cause a newly diagnosed condition called ACDC (arterial calcification due to CD73 deficiency).

The rare condition (ACDC has been identified in nine individuals) arises in adulthood and causes painful arterial calcification in the hands and feet but does not affect the coronary arteries.

"This is the first novel disease discovery identified through the collaborative and interdisciplinary approach employed by clinical researchers in the NIH Undiagnosed Diseases Program," NIH Director Francis Collins said in a statement. "This disorder previously baffled the medical field and evaded diagnosis when conventional methods were used."

As GenomeWeb Daily News reported in 2008, the UDP is funded with $280,000 per year from the NIH Office of Rare Diseases, and the program will primarily use resources, technology, and expertise already found within the institutes.

The interdisciplinary UDP program receives patients through medical referrals from around the country from cases that stump the medical community at large and are not well defined or explained in medical literature. Patients in the program are brought to the NIH Clinical Center in Bethesda, Md., for a range of tests, which in this case included genetic analysis that found mutations in the NT5E gene.

The NIH scientists focused on five members from two families that have the disorder, analyzing DNA from all members of the family in order to compare the parents' DNA to the affected children. The researchers used a combination of SNP analysis, targeted gene sequencing, quantitative PCR assays, among other methods and discovered certain regions in the siblings' genomes where they had two copies of a particular segment of DNA, whereas the parents had just a single copy.

That finding confirmed the researchers' suspicion that ACDC is caused by a recessive inheritance of a mutation in the NT5E gene, which makes the CD73 protein. That protein produces adenosine, which protects arteries from calcifying.

"This study shows that genomic tools are a powerful ally in our search to discover and understand rare diseases," NHGRI Director Eric Green said.

"The diagnosis of this faulty gene is the first molecular description of this disorder," said Manfred Boehm, a National Heart, Lung, and Blood Institute investigator and lead author on the study, which appears in the New England Journal of Medicine this week.

"In addition to providing insight for this unique patient group and their physicians, the study has placed this condition among disorders it resembles, adding to our knowledge of vascular biology," Boehm explained.

Joining NHGRI and NHLBI scientists in conducting the study were researchers from the NIH Office of Rare Disease Research; the NIH Clinical Center; St. John the Baptist Hospital, Turin, Italy; University of California, San Francisco; and Great Ormond Street Hospital-University College, London.