Prevalence, Characteristics and Clinical Diagnosis of Maturity Onset Diabetes of the Young Due to Mutations in HNF1A, HNF4A, and Glucokinase: Results From the SEARCH for Diabetes in Youth

Pihoker, Catherine; Gilliam, Lisa K.; Ellard, Sian; Dabelea, Dana; Davis, Cralen; Dolan, Lawrence M.; Greenbaum, Carla J.; Imperatore, Giuseppina; Lawrence, Jean M.; Marcovina, Santica M.; Mayer‐Davis, Elizabeth J.; Rodríguez, Beatriz L.; Steck, Andrea K.; Williams, Desmond E.; Hattersley, Andrew T.

doi:10.1210/jc.2013-1279

Cited by 347 publications

(319 citation statements)

References 32 publications

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“…Our main finding that at least up to 6.5% of antibody-negative children with diabetes have MODY is somewhat lower than the proportion reported in other studies [11][12][13][14]. Still, our data might be more robust.…”

Section: Discussioncontrasting

confidence: 75%

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

et al. 2016

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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

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Section: Discussioncontrasting

confidence: 75%

“…Although we and others have estimated the prevalence of monogenic diabetes to be 1.1-4.2% of all children with diabetes [11][12][13][14], no study has yet screened a nationwide population-based cohort in a systematic way.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Therefore, screening approaches are essential to gain estimates of the true prevalence and to identify misdiagnosed MODY patients to ensure they benefit from optimal treatment. To date, several studies have screened whole paediatric clinic populations and have estimated MODY to represent between 1.1% and 4.2% of all children with diabetes [7][8][9][10]. The SEARCH for Diabetes in Youth study has been the largest to date [9], using a systematic approach, sequencing genomic DNA from 586 children who were negative for islet autoantibodies and had a fasting C-peptide >0.8 ng/ml.…”

Section: Recognising Mody Is Difficultmentioning

confidence: 99%

“…To date, several studies have screened whole paediatric clinic populations and have estimated MODY to represent between 1.1% and 4.2% of all children with diabetes [7][8][9][10]. The SEARCH for Diabetes in Youth study has been the largest to date [9], using a systematic approach, sequencing genomic DNA from 586 children who were negative for islet autoantibodies and had a fasting C-peptide >0.8 ng/ml. In this study, mutations for the three main MODY genes (HNF1A, HNF4A or GCK) were identified in 8% of the cohort, suggesting an overall population prevalence of 1.2%.…”

Section: Recognising Mody Is Difficultmentioning

confidence: 99%

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Towards a systematic nationwide screening strategy for MODY

Shields

Colclough

2017

Diabetologia

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MODY is an early-onset monogenic form of diabetes. Correctly identifying MODY is of considerable importance as diagnosing the specific genetic subtype can inform the optimal treatment, with many patients being able to discontinue unnecessary insulin treatment. Diagnostic molecular genetic testing to confirm MODY is expensive, so screening strategies are required to identify the most appropriate patients for testing. In this issue of Diabetologia, Johansson and colleagues

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Monogenic Causes of Diabetes

Misra

Hattersley

2016

Textbook of Diabetes

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Prevalence, Characteristics and Clinical Diagnosis of Maturity Onset Diabetes of the Young Due to Mutations in HNF1A, HNF4A, and Glucokinase: Results From the SEARCH for Diabetes in Youth

Cited by 347 publications

References 32 publications

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

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

Towards a systematic nationwide screening strategy for MODY

Monogenic Causes of Diabetes

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