Application of genomics technology in the study of human disease.

Genomic technologies are helping advance our understanding of human diseases at a very fast pace, especially in the fields of cancer, auto inflammatory diseases as well as immunodeficiencies. High throughput technology permits to survey the entire genome and assess individuals genetic variation. This application has proven successful in identifying causal genes in Mendelian diseases and has also provided insight into the genetic etiology in complex diseases. In the past, we have applied applied blood transcriptional profiling to identify biomarkers and therapeutic targets such as IL-1B for patients with systemic onset juvenile idiopathic arthritis (sJIA), one of the major causes of chronic inflammatory arthritis in children. Indeed, clinical trials to evaluate the effect of blocking IL-1B in this disease have proven successful. This discovery supports that sJIA belongs to the recently described category of autoinflammatory diseases, which share similar clinical phenotypes and respond to IL1 blockade. Most autoinflammatory diseases have been described as Mendelian diseases affecting different genes in the IL-1B pathway. In the work presented here, we investigated a potential genetic basis for sJIA, which is a sporadic disease. We applied high throughput next generation sequencing technology to survey the known coding regions of the human genome, the exome, in 6 sJIA trios (individual patients and parents) and in an additional group of 11 patients. In the analysis of trios we identified several potentially pathogenic variants in genes involved in biological functions associated with IL1; we also found mutations in genes shared by two or more sJIA patients. In addition, a rare variant was found in the S100A12 gene, which encodes a biomarker and potential pathogenic factor in the disease, in one family. Overall, our study revealed potential genetic models of compound heterozygous and/or multigenic inheritance in this complex and heterogeneous disease.