Predisposition Genes in Monogenic Diabetes (DIAMONO)

There are several monogenic disorders of pancreatic beta-cell function, characterized by various degrees of chronic hyperglycemia. They are usually diagnosed early in life, in neonates or during infancy, childhood or even in young adults. These diseases comprise a broad spectrum of diabetic phenotypes including neonatal diabetes mellitus (NDM), non auto-immune diabetes in infancy, dominantly inherited forms of early-onset diabetes [also named Maturity-Onset Diabetes of the Young (MODY)] and very rare diabetes-associated syndromes.

So far, causal mutations in more than 20 genes that are highly expressed in the pancreatic beta-cells have been identified in NDM and MODY. These discoveries have demonstrated several aetiological mechanisms of beta-cell dysfunction that are involved in distinct subtypes of monogenic diabetes, including reduced beta-cell number or development (as for mutations in PDX1, PTF1A, HNF1B), reduced glucose sensing and metabolism (mutations in GCK, INS, HNF1A, HNF4A), failure of membrane depolarization (mutations in KCNJ11, ABCC8) and increased destruction of the beta-cell (mutations in INS, EIF2AK3, WFS1), which result in inadequate insulin secretion despite a chronic hyperglycemia. Additional unknown MODY loci may be responsible for 20-30% of the early-onset diabetes cases with a dominant pattern of inheritance, and a proportion of 50% of the NDM/MDI patients are still unelucidated, suggesting that defects in further pathways in the insulin-secreting beta-cell are responsible for monogenic diabetes.

The investigators project is to collect of 15 MODY-X families. This collection will allow the search of novel genes involved in MODY diabetes. The establishment of the cohort will be based on the recruitment of families of MODY-X probands analyzed in the Department of Genetics (Pitie-Salpetriere hospital). This laboratory performs the genetic testing of MODY. To select families eligible to that project, the investigators will apply the following criteria : (i) probands negative for GCK/MODY2 , HNF1A/MODY3 genes and HNF4A/MODY1; (ii) dominant inheritance of diabetes (three consecutive affected generations, or two generations with at least 2 diabetic patients in a generation); (iii) Diagnosis of diabetes before age 40 years in at least 3 diabetic family members; (iv) negative testing for anti-GAD and IA2-antibodies; and (v) body mass index < 30 kg/m2 (to avoid inclusion of patients with insulin-resistant type 2 diabetes).

The investigators will collect clinical information for the selected cases and families of interest according to a standardized questionnaire.

DNA samples will be collected for diabetic family members and healthy relatives. All will sign an informed written consent.