Mulhern, Ciara Maria; (2020) Identification of novel genetic mutations leading to rare monogenic inflammatory diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Over the past 20 years, an increasing number of monogenic inflammatory diseases have been described. In particular, monogenic autoinflammatory disorders are characterized by episodic and unprovoked inflammation, without the existence of high-titre autoantibodies or antigen specific T cells. When such diseases occur early in infancy, the cause is often suspected to be genetic. The emergence of nextgeneration genetic sequencing technologies has provided a fast and reliable means upon which to investigate causative genes, leading to the discovery of novel monogenetic autoinflammatory diseases. This technology also aids our understanding of the molecular pathways underpinning these disorders. The aims of this PhD project were to discover novel genetic causes of inflammatory diseases through the use of next generation sequencing and to explore the functional relevance of identified variants in candidate genes. In this thesis, a cohort of children with suspected monogenic inflammation were subject to next-generation sequencing. Several discoveries were made, and various families are discussed herein. For the first family, the index case was an 8 year old girl suffering from severe neuroinflammation manifesting as left sided focal seizures, left sided hemiplegia, granulomatous cerebral inflammation and chorioretinitis. I identified a rare missense p.T647P mutation in the TNFAIP3 gene as the cause of her predominantly neurological presentation. I was then able to show that this variant induces activation of NF-ƙB pathway and enhances NLRP3 inflammasome activity, but also results in significant upregulation of type I interferon signaling pathway. Targeted therapeutic intervention through administration of a Janus kinase inhibitor, resulted in a complete resolution of neuroinflammation and improvement in her clinical presentation. The second family was a consanguineous Pakistani family, where 3 affected individuals were suffering from a systemic inflammatory disorder characterized by fevers, susceptibility to viral infection, rashes, and haemophagocytosis. I identified a homozygous p.M228K mutation in CCR7 in all affected individuals. Functional experiments showed decreased expression of the CCR7 protein in all affected individuals and defective migration of immune cells following chemokine stimulation. Immunophenotyping also revealed complete absence of central memory T cells and defective IFNγ production in response to viral and bacterial stimuli. Lastly, a homozygous p.D118N mutation in BTNL2 was discovered in the third family I studied, a consanguineous family from Somalia wherein affected individuals were suffering from a familial leukocytoclastic vasculitis. Therefore, through the use of next generation sequencing, coupled synergistically with pertinent functional readouts, I have identified and characterised three novel monogenic immunological diseases, each associated with varying degrees of autoinflammation and immune deficiency.

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