An observational study in Diabetes Mellitus, Type 1, Monogenic Diabetes and Neonatal Diabetes, sponsored by McGill University Health Centre/Research Institute of the McGill University Health Centre. Recruiting at 1 site in Canada. Open to participants aged 1 Day to 25 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-12-10.
Sponsored by McGill University Health Centre/Research Institute of the McGill University Health Centre · Observational
The study has two aims:
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.
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.
10,925 studies on the registry are indexed under Diabetes Mellitus; 1,319 are open to participants now.
This study's planned enrollment of 5,000 is above the median of 233 across 2,220 observational studies indexed under Diabetes Mellitus.
Browse Diabetes Mellitus studies →McGill University Health Centre/Research Institute of the McGill University Health Centre is the lead sponsor of 415 studies on the registry; 106 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Cases diagnosed as type 1 diabetes or undetermined type.
Exclusion Criteria:
Patient has been found negative for at least three T1D antibodies. The investigators will proceed with whole exome sequencing
Other: None AHT
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.
Other: None AHT
No further intervention planned for either group as part of the current study.
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.
Time frame: 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.
Time frame: 7 years
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.
Time frame: 5 years
Plan to share: Yes — Anonymized exome data will be deposited in publicly available databases.15
Supporting information: Study protocol, Sap, Analytic code
No publications or documents are linked to this record.
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Wolfram Syndrome
McGill University Health Centre/Research Institute of the McGill University Health Centre