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Making a definitive diagnosis through whole genome sequencing: A rare event or a thing of the future

I recently came across this paper in Genetics in Medicine, entitled ‘Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease’. A remarkable study worth sharing.

The paper reports a young boy battling with an inflammatory bowel disease-like illness. Treatment defined for patients with Crohn disease did not work and despite various immunosuppressive therapies, the child was never in remission for more than a few months. At the age of 4, the boy weighed just 20 lbs and was severely mal- nourished. The clinical team explored whether the boy might have genetic mutations in a number of known congenital immune deficiencies but drew a blank.

They turned to whole exome sequencing from 5ug of the patient’s genomic DNA. They identified 16,000 mutations,14,597 of which were known, when compared to the human genome reference sequence, while 1,527 were novel. One of these novel variants was in a gene known as X-linked inhibitor of apoptosis (XIAP). Known mutations of XIAP are known to cause XLP2, X-linked lymphoproliferative syndrome but previous cases of XLP2 have not previously been associated with Crohn-like symptomatology. They treated the condition with allogeneic stem cell transplantation, the treatment recommended for XLP, and having found that, before the transplant, the only way to keep the boy in remission was complete bowel rest, it was a remarkable observation when the boy started enteric then oral food at>40 days post transplantation. A rare, albeit clinically satisfying outcome and highlights the advantages of whole genome sequencing, over and above candidate sequencing

Julie Barnes
February 2011

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