Cryptogenic Disease and 'Omics Profiling

An interesting and exciting case report will be published in the March edition of Genetics in Medicine (Worthey et al., Genet Med. 2011 Mar, 13(3):255-262). This Brief Report describes the case of a 6-year old boy in Wisconsin suffering from multiple intestinal fistulas. Despite comprehensive clinical evaluations and a battery of tests, the boy's physicians were unable to arrive at a definitive diagnosis and were baffled at a syndrome that had not been seen before. Clinical management was limited, making it difficult for the boy to eat solid food. After over 100 surgeries the boy only grew sicker and the physicians were at a loss. It was at this point that they carried out whole-exome sequencing. It was discovered that the boy had a mutation in his XIAP gene, a mutation not previously associated with the boy's condition but that had been linked with another pathology which was curable by bone-marrow transplantation. The team performed a bone-marrow transplant (which they would not have considered without the sequencing) and saved the boy's life.

This report, as well as a couple of other recent examples from the literature, raises the question of the role of genomics, proteomics, and metabolomics in initiating treatment regimens for cryptogenic disease. Clearly, this is a striking example of the clinical benefit of sequencing a patient with a poorly understood syndrome. Here, sequencing led to treatment insights that would have been otherwise difficult to arrive at. In the context of this particular case study, it is unclear that proteomic and metabolomic profiling would have offered much clinical benefit. Although metabollite profiling may be useful in diagnosing diseases for which biomarkers have been elucidated, would metabolomics be useful to investigate rare cryptogenic cases such as those described here? At this time, it is difficult to imagine learning much interesting information by doing "metabolite profiling" on a single individual without appropriate controls and statistics. But perhaps this is something that may change with the evolution of our understanding of the human metabolome and the development of much more advanced metabolite databases. For now, metabolomics might be better suited for providing pathobiological insight when it comes to dealing with rare cryptogenic disease.