SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item Restricted Analysis of Whole Exome Sequencing (WES) data in patients with Sjogren’s disease(The University of Manchester, 2024) Alhamdan, Ruqayyah Salman; Rice, GillianAbstract 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.30 0Item Restricted Identification and Functional Characterization of Novel Variants Associated with Sepsis Identified by Whole Exome Sequencing(Saudi Digital Library, 0098-11-04) Alsaif, Hessa Saad; Knight, Julian; Jia, AliciaBackground Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a leading cause of global mortality. Although sepsis is not considered a classic monogenic trait, there is strong evidence of the role of genetics in its susceptibility. Methods and Results This project uses the previously collected sepsis-affected cohort of 484 whole-exome sequenced (WES) samples to bring insights into genetics of sepsis. The two variants in GNLY gene encoding for antimicrobial peptide granulysin, NM_006433.5:c.255+2T>C and NM_006433.5:c.304C>T, have been prioritised using in silico variant pathogenicity prediction tools for further in vitro evaluation. These variants were present in three patients from sepsis cohort. The criteria for prioritisation were the rarity of the variants in non-affected population, the high impact consequences of the variants on GNLY transcripts and proteins, and the essential role of the GNLY gene as a key component of the immune response. NM_006433.5:c.304C>T variant introduces a premature stop codon and is predicted to lead to truncation of GNLY protein by third: from 148 aa to 102 aa. NM_006433.5:c.255+2T>C variant was predicted to affect splicing of exons 3-4 of GNLY transcript. The presence of the variants in three patients from the cohort in a heterozygous state has been confirmed through Sanger sequencing. In vitro ExonTrap minigene assays have confirmed that NM_006433.5:c.255+2T>C variant leads to aberrant splicing. It has been also investigated whether the two variants are presented in compound heterozygote state using cloning assay. The overall conclusion was that the variants are not likely to be present in the compound heterozygote state in two patients. Conclusion Potential of GNLY being a novel sepsis-susceptibility gene, caveats of variant pathogenicity predictions and the potential genetic mechanisms by which the two variants can contribute to the genetics of susceptibility of sepsis are further discussed.16 0