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Next-generation sequencing defines new pathway for blood vessel disease

National Institutes of Health researchers have identified gene variants that cause a rare syndrome of sporadic fevers, skin rashes and recurring strokes, beginning early in childhood. The teams discovery coincides with findings by an Israeli research group that identified an overlapping set of variants of the same gene in patients with a similar type of blood vessel inflammation.

A variation in the gene that makes a key blood vessel enzyme makes children prone to fevers, rash and strokes.

The NIH group first encountered a patient with the syndrome approximately 10 years ago. The patient, then 3 years old, experienced fevers, skin rash and strokes that left her severely disabled. Because there was no history of a similar illness in the family, the NIH group did not at first suspect a genetic cause, and treated the patient with immunosuppressive medication. However, when the NIH team evaluated a second patient with similar symptoms two years ago a child who had experienced recurrent fevers and six strokes by her sixth birthday they began to suspect a common genetic cause and embarked on a medical odyssey that has led not only to a diagnosis, but to fundamental new insights into blood vessel disease.

In their study, which appears in the Feb. 19, 2014, advance online edition of the New England Journal of Medicine, the researchers describe how next-generation genome sequencing, only recently available, facilitated a molecular diagnosis for patients in their study. The researchers found that harmful variants in the CECR1 gene impede production of a protein vital to the integrity of healthy blood vessel walls.

This discovery is another example of genome sequencing playing a central role in revealing the genomic basis for an important rare disease, said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), where the lead members of the research team are based. Such studies illustrate how genomics is paving the way to improved human health.

The researchers showed that faulty variants in their patients DNA that encode the CECR1 gene cause a loss of function of the genes ability to produce of an enzyme called adenosine deaminase 2 (ADA2). Without it, abnormalities and inflammation in blood vessel walls result. The researchers call the new syndrome, deficiency of ADA2, or DADA2. The enzyme ADA2 is chemically similar to the enzyme ADA1, whose deficiency results in severe combined immunodeficiency disease.

NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., led the team of collaborators from NIH and beyond in mounting the study of nine patients. It has been incredibly fantastic to see this kind of progress being made within the last decade, he said. Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population.

For children, as with adults, stroke can affect physical, cognitive and emotional functioning. Some outcomes, such as blindness and deafness, can be lasting; others, such as the ability to walk, can be relearned.

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