Whole-Exome Sequencing in Family Trios Reveals De Novo Mutations Associated with Type 1 Diabetes Mellitus

SIMPLE SUMMARY: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition in which the immune system destroys insulin-making cells in the pancreas. Many advances have been made in the past decade to understand the pathophysiology of T1DM. With an estimated heritability risk of 50%, the strong genetic component plays an important role in the discovery of novel disease pathways and identification of new targets for therapeutic purposes. In this study, we aim to identify new (de novo) genetic markers for T1DM patients by sequencing the genes of the affected individual and their parents (trio family). This is a powerful approach to identify causal mutations for inherited diseases, such as T1DM, to improve our understanding of the condition. With 13 trio families, we identified 32 new (de novo) genetic mutations. Of these, 12 variants that were linked to T1DM, and the remaining 20 variants were linked to endocrine, metabolic, or autoimmune diseases. The findings of this study have allowed us to identify the genetic markers associated with the development of T1DM, to be able to improve diagnosis through therapeutic advancements. ABSTRACT: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency and loss of pancreatic islet β-cells. The objective of this study is to identify de novo mutations in 13 trios from singleton families that contribute to the genetic basis of T1DM through the application of whole-exome sequencing (WES). Of the 13 families sampled for this project, 12 had de novo variants, with Family 7 having the highest number (nine) of variants linked to T1DM/autoimmune pathways, whilst Family 4 did not have any variants past the filtering steps. There were 10 variants of 7 genes reportedly associated with T1DM (MST1; TDG; TYRO3; IFIHI; GLIS3; VEGFA; TYK2). There were 20 variants of 13 genes that were linked to endocrine, metabolic, or autoimmune diseases. Our findings demonstrate that trio-based WES is a powerful approach for identifying new candidate genes for the pathogenesis of T1D. Genotyping and functional annotation of the discovered de novo variants in a large cohort is recommended to ascertain their association with disease pathogenesis.