Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry

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 Henrik U. Irgens, Janne Molnes and Paweł Sztromwasser contributed equally to the study. Stefan Johansson and Pål R. Njølstad share joint senior authorship.Electronic supplementary material The online version of this article

Towards a systematic nationwide screening strategy for MODY

“…In this edition of Diabetologia, Johansson and colleagues describe the first nationwide systematic screening programme for MODY [12]. The Norwegian Childhood Diabetes Registry (NCDR) captures over 96% of children diagnosed with diabetes making it an ideal population for a national study.…”

Monogenic disorders of glucose-stimulated insulin secretion: massively parallel sequencing approaches

“…Screening might be of greater cost benefit in populations with higher prevalence of MODY e.g. those with antibody-negative T1DM [227]. However, as routine testing is so dominant in terms of cost and QALY, it may be unnecessary to assess antibody status for routine screening to remain cost-effective (although we have not modelled this specifically).…”

“…One previous study has specified their criteria for variant classification. Johansson et al [227] used a similar classification system to ACMG (as we have used here), although pathogenicity was determined using a system developed for cancer susceptibility genetic testing [241]. Other papers have not explicitly defined their criteria for allocating pathogenicity, which may contribute to the varying prevalence rates reported for MODY [23,242].…”

“…Two recent studies have used MPS to screen a clinic-based diabetes population. Both used targeted sequencing of all currently known MODY genes but also only sequenced antibody negative (Ab−) cases [23,227]. Thus, to date, there has not been comprehensive screening of a complete pediatric diabetes population.…”

“…We considered the impact of testing in a population with MODY prevalence ranging from 1% to 6.5%, which reflects the prevalence of MODY in an antibody-negative T1DM population [227]). We used estimates from the published literature for ranges around the proportions for each MODY subtype, based on reports from two population-based studies, one using traditional sequencing, and one using MPS [227,247]. Given the paucity of data on the percentage of individuals with MODY successfully converted to SU, an arbitrary range of 50-100% was chosen.…”