Predisposition Genes in Monogenic Diabetes (DIAMONO) (DIAMONO)

Constitution of a Cohort of Families With Monogenic Diabetes to Identify Novel Causes of Non Auto-immune Diabetes Mellitus in Children and Young Adults

Monogenic diabetes accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 diabetes or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. These monogenic diabetes result from gene mutations that reduce beta-cell function. To date, about 20 genes involved in insulin-secretion pathway hav been identified; they correspond to a broad of two main clinical conditions [neonatal diabetes mellitus (NDM) and Maturity-Onset Diabetes of the Young (MODY)]. However, it still remains subtypes of monogenic diabetes that are unelucidated. The investigators project focus on families with a clinical and familial history highly suggesting a MODY diabetes but without genetic etiology. The investigators objective is to set up a collection of families with at least three family members presenting a MODY diabetes.

Study Overview

• Status: Completed
• Conditions: Non Autoimmune Monogenic Diabetes
• Intervention / Treatment: Genetic: blood sample

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 96

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Diabetic family members and healthy relatives

Description

Inclusion Criteria:

• No mutations in known genes associated with MODY (GCK, HNF1A, HNF4A)
• ≥ 3 cases of diabetes in the family over several generations
• An age at diagnosis of diabetes <40 years for 3 subjects diabetics in the family
• Absence of anti-GAD and anti-A2 of antibodies
• No argument for type 2 diabetes

Exclusion Criteria:

• Diabetic subjects
• Healthy subjects whose relationship is relevant for genetic analysis and necessary for the validation step (family cosegregation study)
• These subjects will be over the age of 18, affiliated to a social protection scheme or copyright holder and will signed an informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Diabetic family members; (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).	Genetic: blood sample
Healthy relatives; Healthy subjects whose relationship is relevant for genetic analysis and necessary for the validation step (family cosegregation study)	Genetic: blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of novel predisposition gene	Identification of pathogenic mutations segregating with the "diabetes" phenotype and absent in unaffected relatives.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between genotype and age at diagnosis		1 day
Correlation between genotype and BMI		1 day
Correlation between genotype and treatment		1 day
Correlation between genotype and mode of presentation		1 day
Correlation between genotype and complications of diabetes		1 day
Correlation between genotype and fasting plasma glucose		1 day
Correlation between genotype and HbA1c	at diagnosis and at last examination	1 day

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Christine BELLANNE-CHANTELOT, PharmD-PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: October 5, 2015
• First Submitted That Met QC Criteria: December 15, 2015
• First Posted (Estimate): December 17, 2015

Study Record Updates

• Last Update Posted (Estimate): February 17, 2016
• Last Update Submitted That Met QC Criteria: February 15, 2016
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: insulin secretion; MODY; monogenic diabetes; beta-cell
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus
• Other Study ID Numbers: NI11010