Monogenic Diabetes Misdiagnosed as Type 1
Monogenic Diabetes Misdiagnosed as Type 1
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.
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.
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