Kammermeier, Jochen; (2021) Phenotypic stratification and molecular characterisation of inflammatory bowel disease presenting in early childhood. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Genome wide association studies in inflammatory bowel disease (IBD) highlighted the contribution of common genetic variants to the disease pathogenicity of IBD. Overall combined genetic variation in IBD across the age spectrum however still fails to explain the majority of IBD heritability. First publications of young children with IBD-like phenotype due to underlying monogenic diseases affecting the immune system raised the awareness of Mendelian disorder associated IBD (MDIBD). Although overall rare, the clinical impact of a timely molecular diagnosis was evident for individual patients with immune deficiencies amenable to curative haematopoietic stem cell transplantation. In my research, I investigated the phenotype of IBD presenting in early childhood and evaluated novel next generation sequencing (NGS) platforms to screen for MDIBD. My research led to the first publication of targeted gene panel sequencing (TGPS) for children with suspected MDIBD. The North-East Thames Regional Genetic Laboratory has since integrated TGPS into the routine clinical work up for young children with IBD. I have subsequently analysed transcriptomic data from peripheral blood mononuclear cells and gut biopsies. My results suggest that transcriptomics can highlight the biological compartment affected by a pathogenic variant in patients with MDIBD. Being part of an international working group, we were able to curate and publish the first comprehensive list of MDIBD genes and to establish phenotypic features suggestive of underlying monogenic disease. The main emphasis for the future is to ensure genomic screening is made available for all patients with suspected MDIBD. This will require optimised work flows and the development of national expert hubs to interpret genetic results and feedback clinically relevant information to enable best possible clinical outcome for our patients. Furthermore, we need to strengthen international MDIBD initiatives, to develop a unified nomenclature and facilitate multicentre research into rare monogenic conditions with IBD-like phenotype.

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