title: Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry.
abstract: MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes.
  
  
  
  Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic).
  
  
  
  We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10-5). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5.
  
  
  
  This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bente B
authors.initials: BB
authors.lastname: Johansson
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Department of Paediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Henrik U
authors.initials: HU
authors.lastname: Irgens
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Janne
authors.initials: J
authors.lastname: Molnes
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Paweł
authors.initials: P
authors.lastname: Sztromwasser
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ingvild
authors.initials: I
authors.lastname: Aukrust
authors.affiliation: Department of Paediatrics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Petur B
authors.initials: PB
authors.lastname: Juliusson
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Department of Paediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Oddmund
authors.initials: O
authors.lastname: Søvik
authors.affiliation: Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Torild
authors.initials: T
authors.lastname: Skrivarhaug
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.|Institute of Health and Society, University of Oslo, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Joner
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway. pal.njolstad@uib.no.|Department of Paediatrics, Haukeland University Hospital, Bergen, Norway. pal.njolstad@uib.no.
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008049:Lipase / Q000235:genetics; D008297:Male; D009664:Norway; D051761:Paired Box Transcription Factors / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D064233:Sulfonylurea Receptors / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics; D000099161:Kcnj11 Channel
chemical_list: D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D008049:Lipase; D051761:Paired Box Transcription Factors; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D064233:Sulfonylurea Receptors; D015534:Trans-Activators; D019061:src-Family Kinases; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C115117:KLF11 protein, human; C093970:NEUROD1 protein, human; C491709:PAX4 protein, human; C084010:pancreatic and duodenal homeobox 1 protein; C584409:BLK protein, human; C054621:CEL protein, human
keywords: Antibody-negative; Childhood-onset diabetes; Genetic screening; MODY; Monogenic diabetes; Norwegian Childhood Diabetes Registry; Prevalence; Sulfonylurea