Monogenic Diabetes Misdiagnosed as Type 1 (ADDAM)

Accurate Diagnosis of Diabetes for Appropriate Management

The study has two aims:

1. To (1a) determine the frequency of monogenic diabetes misdiagnosed as type 1 diabetes (T1D) and (2) to define an algorithm for case selection.
2. To discover novel genes whose mutations cause monogenic diabetes misdiagnosed as T1D.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 1; Wolfram Syndrome; Neonatal Diabetes; Monogenic Diabetes; Maturity-onset Diabetes in the Young (MODY); Wolcott-Rallison Syndrome; Mitochondrial Diabetes

Detailed Description

Aim 1. The investigators will recruit 5,000 cases diagnosed as T1D under the age of 25, from 17 participating clinics across Canada. All cases will be tested for four antibodies (against proinsulin, GAD65, islet antigen 2 (IA-2), and ZnT8). Cases negative for all four will be exome-sequenced.

1. Variant annotation will be focused on known monogenic diabetes genes. Variants rated as pathogenic, likely pathogenic or of unknown significance whose zygosity fits the genetic model, will be confirmed in a clinically certified laboratory and communicated to the treating health care team. End-point is the frequency of such variants compared to their frequency in control, non-T1D exomes.
2. The following variables will be examined for the ability to predict monogenic diabetes: Negativity for all autoantibodies tested, family history, polygenic T1D risk score, age of onset, sex, glycosylated hemoglobin (HbA1c), insulin dose, and presence of syndromic features. Predictors will be analyzed by multiple regression and results subjected to jackknife (leave-one-out) validation. Machine-learning techniques may be used.

Aim 2. Variants outside known genes in non-diagnostic exomes will be annotated and examined under autosomal dominant, recessive, X-linked and mitochondrial inheritance models. Corresponding frequency cutoffs will be 0.0005, 0.01, 0.001 and 0.0005 (if heteroplasmy >70%). Formal mutation-burden analysis will be based on depth-adjusted data from the Genome Aggregation Database (gnomAD). Genes mutated in more than one unrelated proband will be examined by a statistical approach taking into account the presence of a large number of phenocopies (Akawi et al., Nat Genet. 2015;47:1363-1369). Genes that achieve statistical significance will be tested in additional cohorts with international collaborations.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Constantin Polychronakos, MD; Phone Number: 22866 5144124400; Email: constantin.polychronakos@mcgill.ca
• Study Contact Backup: Name: Luc Marchand, MSc; Phone Number: 22623 5144124400; Email: luc.marchand@gmail.com

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • The Montreal Children's Hospital
      • Contact: Angeliki Makri, MD; Phone Number: 22623 514-934-1934; Email: angeliki.makri@mail.mcgill.ca
      • Contact: Constantin Polychronakos, MD; Phone Number: 22623 514-934-1934; Email: constantin.polychronakos@mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Cases diagnosed as type 1 diabetes or undetermined type.

Description

Inclusion Criteria:

• Diagnosis of diabetes under the age of 25 as either type 1 or undetermined type.

Exclusion Criteria:

• Existing T1D autoantibody testing with a positive result

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Antibody-negative; Patient has been found negative for at least three T1D antibodies. The investigators will proceed with whole exome sequencing
Antibody-positive; Patient has been found to be positive for at least one T1D autoantibody. No further studies will be performed as part of the main study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes.	The exomes of all patients negative for four T1D autoantibodies will be sequenced and pathogenic variants in genes known to cause monogenic diabetes will be called and annotated. The frequency of genes carrying such variants among these patients will be compared to control exomes from public databases.	6 years
Proportion of patients carrying mutations in previously unstudied genes that meet statistical criteria of pathogenicity for monogenic diabetes.	Exomes not found to carry a mutation (per outcome 1) will be analyzed to discover pathogenic variants in novel genes. Genes mutated in more than one unrelated probands will be statistically evaluated to see if variants in these gene occur more frequently than in control exomes. The number of probands that is needed to fulfill this criterion will depend on the gene's tolerance to protein-altering mutations.	7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk-prediction score for monogenic diabetes mutation in antibody negative T1D patients	Composit score with a statistically significant ROC curve for predicting monogenic diabetes in individuals previously diagnosed as T1D. It will be based on age of onset, T1D polygenic risk score. The risk score will aim to predict monogenic diabetes in cases with clinical T1D diagnosis and known to be antibody negative. The scale will be calculated as follows: From the exome sequencing, the investigators will be able to determine genotype at the three most important loci determining risk for autoimmune T1D (HLA, INS and PTPN22).The composite risk score, along with family history, age of onset, HbA1c+4*insulin dose/kg (as proxy for residual beta cell function) will be subjected to logistic regression for an overall risk. The ROC curve will be used to select a point likely to capture most cases unlikely to have autoimmune T1D, sacrificing specificity to maximize sensitivity. Data will be validated with jackknife cross-validation.	5 years

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2019
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 11, 2019
• First Submitted That Met QC Criteria: June 14, 2019
• First Posted (Actual): June 17, 2019

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Eye Diseases; Neurologic Manifestations; Endocrine System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Neurodegenerative Diseases; Ear Diseases; Eye Diseases, Hereditary; Heredodegenerative Disorders, Nervous System; Optic Nerve Diseases; Cranial Nerve Diseases; Sensation Disorders; Optic Atrophies, Hereditary; Optic Atrophy; Pituitary Diseases; Abnormalities, Multiple; Hearing Disorders; Vision Disorders; Deaf-Blind Disorders; Blindness; Hearing Loss; Deafness; Diabetes Insipidus; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Syndrome; Diabetes Mellitus, Type 1; Wolfram Syndrome
• Other Study ID Numbers: ADDAM; Canscreen (Other Identifier: Research Ethics Board, MUHC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized exome data will be deposited in publicly available databases.15
• IPD Sharing Time Frame: 15 years
• IPD Sharing Access Criteria: Approval, by the sponsor, of a research plan that proposes to use the data to promote diabetes research
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No