title: Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young.
abstract: OBJECTIVE
  Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, reportedly accounting for 2% to 5% of all cases of diabetes. In samples from Canadian patients referred for molecular genetic confirmation of a clinically suspected MODY, we determined the prevalence of likely disease-causing DNA variants in known MODY genes.
  
  
  METHODS
  Between 1999 and 2015, our centre received requests from colleagues for DNA sequencing of 96 samples from unrelated Canadian patients with clinically suspected MODY. Prior to 2012, we used Sanger sequencing, and since 2012 we have used targeted next-generation sequencing.
  
  
  RESULTS
  Of 96 samples received, 39 (40.6%) had a likely rare causal variant in 1 of 8 known MODY genes. Of these, 20 (51.3%) and 19 (48.7%) were diagnosed by Sanger and targeted next-generation sequencing, respectively. The 39 mutation-positive samples had 1 of 39 rare variants, of which the majority were in genes encoding either glucokinase (GCK, or MODY2) or hepatocyte nuclear factor 1-alpha (HNF1A, or MODY3). Furthermore, 12 (30.8%) of the detected rare variants had been unreported previously but were likely to have been clinically significant according to standard bioinformatic methods. An additional 6 samples had rare variants in MODY genes that were of uncertain clinical significance.
  
  
  CONCLUSIONS
  The findings suggest that clinical suspicion for MODY has a diagnostic yield of ~40% at the molecular level. Confirmatory genetic testing in patients suspected to have MODY allows for definitive diagnoses which, in turn, may guide management and provide rationales for screening other family members presymptomatically.
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Brahm
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Adam D
authors.initials: AD
authors.lastname: McIntyre
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000235:genetics*; D005500:Follow-Up Studies; D005941:Glucokinase / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011379:Prognosis
chemical_list: D015415:Biomarkers; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D005941:Glucokinase
keywords: corrélation génotype/phénotype; diabète monogénique; genetics; genotype-phenotype correlation; génétique; monogenic diabetes; mutations; next-generation DNA sequencing; séquençage de l'ADN de nouvelle génération