Monogenic Diabetes Misdiagnosed as Type 1 (ADDAM)

McGill University

Status: Enrolling

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

Treatments: Other: None AHT

Study type: Observational

Funder types: Other

Identifiers

NCT03988764

Canscreen (Other Identifier)

ADDAM

Details and patient eligibility

About

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.

Full 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.

Enrollment: 5,000 estimated patients

Sex: All

Ages: 1 day to 25 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

5,000 participants in 2 patient groups

Antibody-negative

Description:

Patient has been found negative for at least three T1D antibodies. The investigators will proceed with whole exome sequencing

Treatment:

Other: None AHT

Antibody-positive

Description:

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.

Treatment:

Other: None AHT