Role of High-Throughput Whole Genome Sequencing for the Diagnosis and Care of Atypical Diabetes
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: WGS coupled with MCM.
- Who it may be relevant to
- Registry conditions: Diabetes Mellitus. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- France
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Overview
The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice, in a randomized trial. Notably, the questions it aims to answer are: * The feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes, * The contribution of WGS coupled with MCM on number of genetic alterations likely causal of diabetes identified and with a modification in care and support of patients. After inclusion and sampling for genotyping, patients will be followed for 5 years. The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.
Detailed description
The prevalence of diabetes is 7.4% in France among people aged 20 to 79 years in 2015. We must also consider \"pre-diabetes\" (subjects with glucose intolerance), whose prevalence is equivalent to that of diabetes (2012 estimate). The incidence of diabetes is exploding both for type 2 diabetes, which represents 85% of diabetes, and for type 1 diabetes, which represents 10% of cases and starts one out of two times before the age of 20. Diabetes typing is essential to guide therapeutic choices, particularly the use of insulin. This typing is based on the pathophysiology of the disease, distinguishing insulinopenia from autoimmune causes in type 1 diabetes, monogenic diabetes, secondary or atypical diabetes and type 2 diabetes, where insulinopenia and insulin resistance coexist. Thus, while a formal biological diagnosis is possible for some forms of atypical diabetes and for type 1 diabetes, no biological parameter is currently available for type 2 diabetes, which remains a diagnosis of exclusion. As a result, diabetes represents a source of diagnostic and therapeutic erraticism, amplified by the clinical heterogeneity of type 2 diabetes, which is obvious and underestimated, and by a clinical phenotyping of patients that is often defective. The economic consequences are important because the health costs are very different depending on whether or not patients are treated with insulin. Type 1 and type 2 diabetes are examples of chronic, non-transmissible, multigenic, multifactorial diseases. However, less than 10% of the heritability of type 2 diabetes is currently explained by the associated genetic variants. And although genetic tests exist to diagnose certain monogenic diabetes, this diagnosis is made in less than 20% of cases, mainly in the presence of an atypical clinical presentation of diabetes. Moreover, there is no reason to rule out the hypothesis of paucigenic forms, at the interface of monogenic diabetes and multigenic forms as usually envisaged, as has been observed in chronic pancreatitis, which is also accompanied by diabetes.
The study will be conducted according to a randomized trial design comparing two diagnostic strategies defined as follows:
* Control strategy: in silico analysis of a panel of validated genes (ISApanel - Diabetome 1). Patients recruited along the control procedure will stay in their group using current genetic diagnosis practices and standard of care that may differ from one center to another. * Intervention strategy: whole genome sequencing coupled with multidisciplinary conciliation meeting.
We plan to randomize one patient in the control group for two in the intervention group.
The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice.
The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.
Interventions
- Diagnostic test WGS coupled with MCM
Whole genome will be screened and analysis will focus on pathogenic and likely pathogenic variants. The list of variants of interest will be recorded until examination and discussion during the MCM. MCM will edit a final synthesis concerning the pathogenicity of identified variants.
Primary outcome measures
- Number of patients with one or several genetic alterations likely causal of diabetes [Time frame: At 6 months in control group and 12 months in interventional group]
Secondary outcome measures (12)
- Number of patients with an impact on treatment modification [Time frame: 5 years]
- Number of genetic alterations likely causal of diabetes [Time frame: At 6 months in control group and 12 months in interventional group]
- Feasibility of the whole genome sequencing (WGS) coupled with multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes: time to access to the genetic data [Time frame: At 6 months in control group and 12 months in interventional group]
- Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and MCM [Time frame: At 6 months in control group and 12 months in interventional group]
- Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and access to WGS report [Time frame: At 6 months in control group and 12 months in interventional group]
- Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and date of the WGS result visit [Time frame: 5 years]
- Genotype-Insulin secretion phenotype association [Time frame: At 6 months in control group and 12 months in interventional group]
- Genotype-Insulin sensitivity phenotype association [Time frame: At 6 months in control group and 12 months in interventional group]
- Genotype-body composition phenotype association [Time frame: At 6 months in control group and 12 months in interventional group]
- Glycemic control without insulin treatment [Time frame: 5 years]
- Glycemic control without severe hypoglycemia [Time frame: 5 years]
- Number of long-term micro and macro vascular complications associated with diabetes and time to occurrence of the first complication [Time frame: 5 years]
Eligibility criteria
Inclusion criteria
- Subjects ≥18 years with confirmed diabetes mellitus according to WHO criteria (World Health Organization: Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF Consultation. Geneva, World Health Org., 2006.)
- Age ≤ 45 years at diabetes diagnosis
- Body mass index ≤ 35 kg/m² at diabetes diagnosis
- Negative results of specific antibodies determination (GAD65, IA2, ZnT8) until the inclusion visit
- Presenting atypical diabetes defined by at least one of the following:
- Exocrine pancreatic disease
- Familial history: diabetes diagnosed in a parent, child or sibling
- Notion of familial consanguinity
- Syndromic clinical features (dysmorphy, developmental delay, mental retardation…) or unusual abnormalities/features that are not part of diabetic complications or co-morbidities;
- Early occurrence of microvascular complications (≤ 5 years after diabetes diagnosis)
- Major insulinopenia at diagnosis (C peptide < 0.2 nmol/L and/or documented ketosis)
- Patient who conserved endogenous insulin secretion (positive C peptide value) but a need for insulin therapy initiation during the first year following diagnosis due to therapeutic failure of well conducted therapeutic intensification
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Patient with a social security number in compliance with the French law (dispositions relatives aux recherches impliquant la personne humaine prévues aux articles L 1121-1 et suivants du Code de la Santé Publique)
- Signed and dated informed consent form
Exclusion criteria
- Pregnant or breastfeeding woman,
- Any contraindication to the study exams including known allergies or contraindication to contrasts for the scan
- Patient with known monogenic diabetes (defined as identification of class 4 and 5 variants according to ACMG)
- First or second-degree relatives with monogenic diabetes established by molecular genetics (class 4 and 5 variants according to ACMG)
- Patient with known secondary diabetes (i.e. endocrine disorders such as Cushing syndrome, pancreatectomy, drug-induced diabetes)
- Patient who had a bone marrow transplant
- Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
- Individuals under legal protection (sauvegarde de justice).
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Open label
- Primary purpose
- Diagnostic
Study locations
France · 26 centers
- University Hospital — Amiens
- University Hospital — Angers
- University Hospital Jean Minjoz — Besançon
- University Hospital Haut Lévêque — Bordeaux
- University Hospital Cavale Blanche — Brest
- Centre Hospitalier Sud Francilien — Corbeil-Essonnes
- University Hospital Bocage — Dijon
- University Hospital Michallon — Grenoble
- … and 18 more centers
Identifiers
NCT: NCT06570278 · C17-27 · 2021-A02597-34