Clinical trial NCT03988764: Monogenic Diabetes Misdiagnosed as Type 1
Official title: Accurate Diagnosis of Diabetes for Appropriate Management
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Diabetes Mellitus, Type 1
Monogenic Diabetes
Neonatal Diabetes
Maturity-onset Diabetes in the Young (MODY)
Wolfram Syndrome
Wolcott-Rallison Syndrome
Mitochondrial Diabetes
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2019-06-17
Enrollment: 5000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Cases diagnosed as type 1 diabetes or undetermined type.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes.
timeFrame: 6 years
measure: Proportion of patients carrying mutations in previously unstudied genes that meet statistical criteria of pathogenicity for monogenic diabetes.
timeFrame: 7 years
Secondary outcomes:
measure: Risk-prediction score for monogenic diabetes mutation in antibody negative T1D patients
timeFrame: 5 years
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: The Montreal Children's Hospital
state: Quebec
Study officials:
References: