Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes

Shepherd, Maggie; Shields, Beverley M.; Hammersley, Suzanne; Hudson, Michelle; McDonald, Timothy J.; Colclough, Kevin; Oram, Richard A.; Knight, Bridget; Hyde, Christopher; Cox, Julian; Mallam, Katherine; Moudiotis, Christopher; Smith, Rebecca; Fraser, Barbara; Robertson, Simon; Greene, Stephen A.; Ellard, Sian; Pearson, Ewan R.; Hattersley, Andrew T.

doi:10.2337/dc16-0645

Cited by 198 publications

(186 citation statements)

References 33 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: 55%

“…Thus, cases diagnosed in outpatient clinics are likely under-represented. Hence, it is not surprising that the frequency of GCK mutations found in our study is much lower than in a recent study performed in clinics with particular MODY awareness [14]. Additionally, the age limit of most children's hospitals in Norway is 15 years of age, which is likely in the lower range of age of diagnosis of MODY.…”

Section: Discussioncontrasting

confidence: 50%

“…Urinary and serum C-peptide levels persist in patients with MODY who retain endogenous beta cell function [28,29]. A recent study from the UK showed that the biomarkers efficiently identify paediatric patients appropriate for genetic screening [14]. These markers have not been included in our routine screening since the analysis in Norway is done when diabetes is detected.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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: 55%

Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…They found 2.5% of patients to have monogenic diabetes. Authors suggested that this biomarker screening algorithm could be a rational and practical approach to identifying pediatric patients who are most suitable for genetic testing (16).…”

Section: Discussionmentioning

confidence: 99%

More than kin, less than kind: one family and the many faces of diabetes in youth

Franco

Peixoto-Barbosa

Dotto

et al. 2017

Arch. Endocrinol. Metab.

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SUMMARYIdentification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin). We found a Gly178Ala substitution in exon 5 of GCK gene in three individuals co-segregating with diabetes, and type 1 diabetes was identified in two other individuals based on clinical and laboratory data. One individual with previous gestational diabetes and other with prediabetes were also described. We discuss difficulties in defining etiology of hyperglycemia in youth in clinical practice, especially monogenic forms of diabetes, in spite of the availability of several genetic, laboratory, and clinical tools. Arch Endocrinol Metab. 2017;61(6):637-42

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Monogenic Causes of Diabetes

Resnick,

Shepherd,

Hattersley

2024

Textbook of Diabetes

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Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes

Cited by 198 publications

References 33 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

More than kin, less than kind: one family and the many faces of diabetes in youth

Monogenic Causes of Diabetes

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