Targeted Next-Generation Sequencing Reveals MODY in Up to 6.5% of Antibody-Negative Diabetes Cases Listed in the Norwegian Childhood Diabetes Registry

Diabetologia. 2017 Apr;60(4):625-635. doi: 10.1007/s00125-016-4167-1. Epub 2016 Dec 2.

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.

Keywords: Antibody-negative; Childhood-onset diabetes; Genetic screening; MODY; Monogenic diabetes; Norwegian Childhood Diabetes Registry; Prevalence; Sulfonylurea.

MeSH terms

  • Adolescent
  • Antibodies / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Cycle Proteins / genetics
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / immunology*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Germinal Center Kinases
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 4 / genetics
  • High-Throughput Nucleotide Sequencing*
  • Homeodomain Proteins / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Lipase / genetics
  • Male
  • Norway
  • Paired Box Transcription Factors / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Repressor Proteins / genetics
  • Sulfonylurea Receptors / genetics
  • Trans-Activators / genetics
  • src-Family Kinases / genetics

Substances

  • ABCC8 protein, human
  • Antibodies
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Germinal Center Kinases
  • HNF1B protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Homeodomain Proteins
  • KLF11 protein, human
  • Kir6.2 channel
  • NEUROD1 protein, human
  • PAX4 protein, human
  • Paired Box Transcription Factors
  • Potassium Channels, Inwardly Rectifying
  • Repressor Proteins
  • Sulfonylurea Receptors
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Hepatocyte Nuclear Factor 1-beta
  • BLK protein, human
  • src-Family Kinases
  • Protein-Serine-Threonine Kinases
  • CEL protein, human
  • Lipase