Bente B Johansson1,2, Henrik U Irgens1,3, Janne Molnes1,2, Paweł Sztromwasser2,4,5, Ingvild Aukrust1,2, Petur B Juliusson3,5, Oddmund Søvik1,3, Shawn Levy6, Torild Skrivarhaug7, Geir Joner7,8, Anders Molven1,9,10, Stefan Johansson1,2, Pål R Njølstad11,12. 1. K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway. 2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. 3. Department of Paediatrics, Haukeland University Hospital, Bergen, Norway. 4. Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway. 5. Department of Clinical Science, University of Bergen, Bergen, Norway. 6. Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA. 7. Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. 8. Institute of Health and Society, University of Oslo, Oslo, Norway. 9. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. 10. Department of Pathology, Haukeland University Hospital, Bergen, Norway. 11. K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway. pal.njolstad@uib.no. 12. Department of Paediatrics, Haukeland University Hospital, Bergen, Norway. pal.njolstad@uib.no.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/ INTERPRETATION: 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.
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