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Neonatal diabetes is a rare, genetically heterogeneous disorder. Mutations in 19 genes are known to cause the disease, including several transcription factors involved in pancreatic development. The aim of this thesis is to comprehensively assess the spectrum and role of mutations in known and novel pancreatic transcription factors in patients with pancreatic agenesis and neonatal diabetes. The first section gives an introduction to neonatal diabetes with a focus on pancreatic transcription factor mutations that cause neonatal diabetes in humans. This chapter is followed by a section describing the main methodologies used throughout the thesis. Biallelic mutations in the pancreatic transcription factor PDX1 have been shown to cause pancreatic agenesis. Chapter 1 investigates the possibility of hypomorphic PDX1 mutations causing isolated permanent neonatal diabetes (PNDM) without pancreatic hypoplasia. We identified 4 such patients, demonstrating that mutations in PDX1 can cause isolated PNDM. Chapter 2 describes the use of exome sequencing to identify novel disease genes, by looking for de-novo mutations in two patients with pancreatic agenesis. Both patients had mutations in the transcription factor gene GATA6. Sequencing of GATA6 in a cohort of 27 patients with pancreatic agenesis identified heterozygous mutations in 13 patients. All 15 patients present additional extra-pancreatic features. In Chapter 3 the role of GATA6 mutations was further investigated in patients with neonatal diabetes, which led to the identification of an additional 14 cases. Familial studies showed that GATA6 mutations can also cause adolescent/adult-onset diabetes. Taken together, these two chapters show that GATA6 mutations cause a variable diabetic phenotype, ranging from pancreatic agenesis, to adult-onset diabetes with or without extra-pancreatic features. Chapter 4 describes three patients with diabetes and chromosome rearrangements deleting GATA4, a transcription factor closely related to GATA6. Mutation analysis of all patients with neonatal diabetes of unknown genetic aetiology identified two additional cases, suggesting that GATA4 mutations are a cause of neonatal and childhood-onset diabetes. Chapter 5 illustrates the use of a targeted capture next-generation sequencing assay to simultaneously investigate all known neonatal diabetes genes in patients with neonatal diabetes of unknown genetic aetiology. This study investigates the impact of early, comprehensive genetic testing in a large international cohort of 1020 neonatal diabetes patients. Chapter 6 summarises the main findings of each chapter, describes their wider impact, and suggests areas of future work. |
