Dec 22, 2010

Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Elizabeth A WortheyDavid Dimmock


We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management. We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management. After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consi...Continue Reading

Mentioned in this Paper

Molecular Diagnosis
X-Linked Inhibitor of Apoptosis Protein
Recurrent Malignant Neoplasm
Whole Exome Sequencing
Gastrointestinal Diseases

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Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

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