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

Genet Med. 2011 Mar;13(3):255-62. doi: 10.1097/GIM.0b013e3182088158.


Purpose: 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.

Methods: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management.

Results: 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, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling.

Conclusions: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Exons
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Infant
  • Inflammatory Bowel Diseases / diagnosis*
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / therapy
  • Male
  • Molecular Sequence Data
  • Mutation
  • Sequence Alignment
  • Sequence Analysis, DNA*
  • Treatment Outcome
  • X-Linked Inhibitor of Apoptosis Protein / genetics


  • X-Linked Inhibitor of Apoptosis Protein