Identification of gene mutations associated with Type 1 Diabetes by Next Generation Sequencing in Inflicted Palestinian Families

Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycemia secondaryto insulin resistance or deficiency. It is considered a major health problem worldwideType 1 diabetes mellitus results due to a combination between genetics, epigenetics, and environmental factors. Several genes have been associated with type 1 diabetes mellitus including human leukocyte antigens, Insulin, Cytotoxic T Lymphocyte Associated Protein 4, and Protein Tyrosine Phosphatase Non Receptor Type 22. However, none of them was based on linkage analysis because it is rare to find families with several diabetic individuals. Two Palestinian families with several inflicted members with variations inthe mode of inheritance were identified and selected for this study. The Aim of this study wasto identify putative causative genes responsible for Type 1 diabetes development in these families toimprove our understanding of the molecular genetics of the disease. One inflicted memberfrom each family was selected for Whole Exome Sequencing. Data were mapped to thereference human genome and the resulting VCF file data was filtered. The variants with thehighest phenotype correlation score were checked by Sanger sequencing in all familymembers. The confirmed variants were in silico analyzed by bioinformatics tools. In onefamily, IGF1R p.V579F variant which follows autosomal dominant inheritance was confirmedand segregated in the family. In another family, NEUROD1 p.P197H variant which followsautosomal recessive inheritance was positively confirmed and segregated. In conclusion,IGF1R p.V579F and NEURID1 p.P197H variants were associated with T1DM development inthe two inflicted families. Further analysis and functional assays will be performed includingthe generation of mutant model cell system to unravel their specific molecular mechanism inthe disease development.