Rice, GillianAlhamdan, Ruqayyah Salman2025-02-252024https://hdl.handle.net/20.500.14154/74928Abstract Background: Connective Tissue Diseases (CTDs) comprise a wide range of immunologic systemic conditions, each characterised by a distinct set of clinical manifestations and specific autoimmune antibodies. Sjogren Syndrome (SS), which falls within the category of CTDs, is an autoimmune condition primarily caused by lymphocytic infiltration in the exocrine glands, resulting in ocular and oral dryness. The primary etiopathogenic mechanism for the development of SS is not fully understood. It is suggested that common genetic backgrounds in combination with environmental factors may contribute to the development of autoimmune diseases. Objectives: This paper aims to analyse Whole Exome Sequencing (WES) files from patients with SS to identify potential disease-causing variants. Methods: Twenty patients with SS were recruited in this study. All WES files were filtered to prioritise potentially disease-causing variants using a balanced scoring system. A gene panel was constructed prior to the scoring system to further assess the genes associated with autoimmune conditions. The patients’ data were compared with controls to ensure the exclusion of common, non-disease-causing variants. The prioritised list of variants was classified by the American College of Medical Genetics and Genomics (ACMG) criteria. Results: WES allowed for the detection of seven rare, potential disease-causing variants in eight patients that were not found in controls: Val367Leu, His140Arg, Arg822Gln, Val377Ile, Ala328Thr, Arg233His, and 798+1G>A, harboured in UNC93B1, RNASEH2B, IFIH1, MVK, TNFAIP3, COPA, AIRE genes, respectively. These genes are primarily related to monogenic autoimmune conditions, with a majority playing a role in increasing the expression of type 1 interferon (IFN-1), causing type 1 interferonopathies (IFNopathies). Conclusions: The scoring system and filtration strategies developed effectively identified potential causative genes for SS. The candidate pathogenic variants could offer valuable insight into the etiological pathways and disease mechanisms associated with SS. Further functional investigations are necessary to understand their role in the pathogenesis of SS.64enConnective Tissue DiseasesType I interferonType 1 interferonopathiesSjogren's DiseaseWhole Exome SequencingThesis