Analysis of immunological and genetic signatures in pediatric inflammatory bowel diseases

In inflammatory Bowel Disease (IBD), consisting of Crohn*s disease and
ulcerative colitis, it is believed that both genetic predisposition and
environmental factors contribute to the etiology. Experimental studies and
genetic evidence suggest that chronic intestinal inflammation is complex and
triggered by various environmental factors, immunological dysfunctions,
defective epithelial barrier function, and imbalances of the microbial flora in
genetically susceptible individuals.
Another sub-population within the IBD group is that of much younger children
diagnosed with very early onset IBD (VEO-IBD) of which the incidence has
dramatically increased over the past decades worldwide. VEO-IBD presents with a
phenotype that is significantly different from the forms observed in adults and
older children. Children with VEO-IBD often fail to respond to conventional
therapies or surgery and its worst forms are life-threatening. Recent studies
have shown that in contrast to IBD diagnosed at a later age, the pathogenesis
of VEO-IBD is expected to be greatly influenced by inherited factors, due to
the young age of onset, increased prevalence of familial disease, and a
phenotype that is significantly different. While the number of genes implicated
in intestinal disease in model organisms is growing rapidly, only few of these
have been systematically tested in human subjects. Many patients with the rare
entity of VEO-IBD show severe refractory and life-threatening diseases,
therefore innovative and comprehensive studies elucidating the underlying
immunological and genetic molecular pathomechanisms are critical. Since VEO-IBD
is a rare condition, centralizing a big international cohort in one laboratory
with state-of-the-art equipment and extensive experience is of great
importance. Furthermore, it is believed that this centralization will offer
substantial understanding of the pathophysiology and subsequently offer novel
targeted treatment therapies.

In this study it is aimed to investigate the genetic and immunological causes
of VEO-IBD in order to improve diagnostics and therapies for patients with this
intractable disease. In an explorative approach, state-of-the-art genome-wide
screenings on genomic DNA and RNA will be conducted in children with VEO-IBD
and their parents (e.g. whole exome sequencing, whole genome sequencing, RNA
sequencing) to detect potential disease-causing mutations. The genetic studies
will be complemented by analysis of the immune system, microbiome, biomarkers,
and environmental factors. It is hypothesized that the genetic and
immunological information gained by this study will ultimately lead to the
development of diagnostic tools and improvements in health care of children
with intestinal diseases.

An international cohort study in order to explore novel genetic variations
associated with VEO-IBD, and to determine the underlying molecular causes of
the disease, which in turn might lead to better targeted (tailored) treatment.

All included VEO-IBD patients will be asked to donate samples containing blood,
saliva, urine, stool, and also additional mucosal biopsies during routine
endoscopy. Furthermore, samples containing blood, saliva, urine and stool will
be obtained from the parents. All of these biospecimens will be send off to
Dr. von Hauner Children's Hospital laboratory in Munich, Germany

A minimal psychological burden and risk is associated with finding out whether
or not a particular family carries a mutation. More specifically there is a
minimal risk of bruising and infection or bowel perforation, when respectively
performing vena puncture or endoscopy. Obtaining other biospecimens show no
risk to the patient or parents. On the other hand, since genetic analysis
(using blood and urine samples) in VEO-IBD patients is part of standard routine
medical diagnostic procedures, participating is also beneficial.