Monogenic Diabetes Misdiagnosed as Type 1

Brief Title

Monogenic Diabetes Misdiagnosed as Type 1

Official Title

Accurate Diagnosis of Diabetes for Appropriate Management

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.
    


Study Type

Observational


Primary Outcome

Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes.

Secondary Outcome

 Risk-prediction score for monogenic diabetes mutation in antibody negative T1D patients

Condition

Diabetes Mellitus, Type 1


Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

5000

Start Date

September 24, 2019

Completion Date

December 31, 2022

Primary Completion Date

December 31, 2022

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
      

Gender

All

Ages

N/A - 25 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

, 5144124400, [email protected]

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT03988764

Organization ID

ADDAM

Secondary IDs

Canscreen

Responsible Party

Sponsor-Investigator

Study Sponsor

Constantin Polychronakos


Study Sponsor

, , 


Verification Date

October 2019