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Clinical Care/Education/Nutrition/Psychosocial Research

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

  1. Beverley M. Shields1,2,
  2. Maggie Shepherd1,2,
  3. Michelle Hudson1,
  4. Timothy J. McDonald1,3,
  5. Kevin Colclough4,
  6. Jaime Peters5,
  7. Bridget Knight1,2,
  8. Chris Hyde5,
  9. Sian Ellard1,4,
  10. Ewan R. Pearson6 and
  11. Andrew T. Hattersley1,2⇑,
  12. on behalf of the UNITED study team
  1. 1Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
  2. 2NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
  3. 3Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
  4. 4Molecular Genetics Diagnostic Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
  5. 5Exeter Test Group, University of Exeter Medical School, Exeter, U.K.
  6. 6Division of Molecular & Clinical Medicine, School of Medicine, University of Dundee, Dundee, U.K.
  1. Corresponding author: Andrew T. Hattersley, a.t.hattersley{at}exeter.ac.uk.
Diabetes Care 2017 Aug; 40(8): 1017-1025. https://doi.org/10.2337/dc17-0224
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    Figure 1

    The UNITED biomarker screening pathway to investigate etiology of diabetes in patients diagnosed at age 30 years or younger. Genetic testing is carried out on all patients who have endogenous insulin (UCPCR ≥0.2 nmol/mmol) and do not have either GAD or IA2 islet autoantibodies. Patients without endogenous insulin or with GAD and/or IA2 islet autoantibodies are classed as having type 1 diabetes.

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    Figure 2

    Flow chart of patients recruited as part of UNITED. Biomarker screening pathway in 1,376 patients with no known genetic cause for their diabetes in Exeter and Tayside. Eleven dropped out. Seventeen new cases of monogenic diabetes detected (*one case identified through exome sequencing).

Tables

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  • Table 1

    Characteristics of patients diagnosed with monogenic diabetes and details of mutations found for those recruited but diagnosed with monogenic diabetes prior to the study and those diagnosed as a result of the biomarker pathway

    IDGenetic characteristicsClinical characteristics
    GeneMethodZygosityDNA level descriptionAge at diagnosis (years)TreatmentParent with diabetesBMIHbA1cAge at recruitment (years)Additional clinical features
    Recruited but diagnosed prior to the UNITED study
     211GCKSangerHetc.97_117dup3DietYes34.04816
     523GCKSangerHetc.97_117dup27DietNo51.75543
     537GCKSangerHetc.683C>T11DietYes13
     538GCKSangerHetc.683C>T9DietYes11
     542GCKSangerHetc.184G>A29DietYes38.94839
     543GCKSangerHetc.184G>A4DietYes4
     544GCKSangerHetc.184G>A3DietYes5
     1155GCKSangerHetc.1343G>T25DietYes19.35025
     82095GCKSangerHetc.1019G>T9DietYes21.94514
     535HNF1ASangerHetc.379_381del24OHAYes25.95147
     547HNF1ASangerHetc.1748G>A22DietYes24.44030Low renal threshold
     554HNF1ASangerHetc.872dup18OHAYes308639
     566HNF1ASangerHetc.872dup17OHAYes29.25142Sulphonylurea sensitivity, low renal threshold
     603HNF1ASangerHetc.1420C>T20OHAYes26.55642Low renal threshold
     617HNF1ASangerHetc.779C>T25DietYes25.44426
     892HNF1ASangerHetc.476G>A14InsulinYes30.06340
     1370HNF1ASangerHetc.872dup21DietYes36.18321
     1409HNF1ASangerHetc.872dup21OHA+InsYes32.89542Sulphonylurea sensitivity
     80480HNF1ASangerHetc.1093_1107+6del19OHA22.97340
     82261HNF1ASangerHetc.185del12OHA+InsYes23.77325Low renal threshold
     82276HNF1ASangerHetc.434C>T13InsulinYes23.86027
     82301HNF1ASangerHetc.1340C>T20OHAYes27.49137
     82310HNF1ASangerHetc.185del18OHAYes24.44845Low renal threshold
     82374HNF1ASangerHetc.1093_1107+6del19OHAYes23.88320Sulphonylurea sensitivity
     82258HNF4ASangerHetc.322G>A28InsulinYes20.96031
     600HNF1BSangerHetc.982_986del20InsulinNo23.412235Renal cysts
     82033HNF1BSangerHetc.466A>G17InsulinNo25.35435Genital tract malformations, renal hypoplasia
     82006KCNJ11SangerHetc.601C>T0OHANo26.63335Diagnosed at 12 weeks of age
     539LMNASangerHetc.1930C>T17OHA+InsYes24.211449Lipodystrophy
     595LMNASangerHetc.1444C>T21OHA+InsYes25.16234
     6043243Hpm.3243A>G27InsulinYes26.95436
     805413243Hpm.3243A>G28InsulinYes26.48348
     823993243Hpm.3243A>G29InsulinYes26.45641Deafness
     540NEUROD1SangerHetc.616dup21OHA+InsYes49.88336Lipodystrophy and necrobiosis
    Identified as part of the biomarker pathway
     82372GCKSangerHetc.1340G>A18DietNo25.54619
     82316HNF4ASangerHetc.1064–5_1070del14DietYes32.33833
     377HNF4ASangerHetc.-12G>A11InsulinYes28.410414
     80089HNF1ASangerHetc.1349dup30InsulinYes31.07248
     80170HNF1ASangerHetc.391C>T21InsulinNo23.55235Low renal threshold
     80173HNF1ASangerHetc.495G>C17InsulinYes24.55646
     82003HNF1ASangerHetc.28A>C26DietYes29.87326
     82352HNF1ASangerHetc.814C>T13InsulinYes32.39145
     82013HNF1AtNGSHetc.-258A>G24OHAYes39.67543
     307HNF1BtNGSHetc.1-?_1674+?del29InsulinNo22.76231Asperger syndrome, renal cysts, low fecal elastase, low magnesium
     82014NEUROD1tNGSHetc.616dup21OHANo35.38831
     183NEUROD1tNGSHetc.616dup29InsulinNo27.15546
     820103243tNGSHpm.3243A>G27OHA+InsYes28.69146
     82038PPARGtNGSHetc.1154G>A22OHANo26.65336Lipodystrophy, acanthosis
     80925TRMT10AtNGSHomc.79G>T23OHA+InsNo33.06928Microcephaly, learning difficulties, epilepsy
     17WFS1tNGSC/Hetc.874C>T & c.877del20Insulinn/k21.84224Bilateral optic atrophy, neurogenic bladder, diet treatment, muscle pain on exercise
     175POLD1ExomeHetc.1812–1814del14OHANo18.63021Total lipodystrophy, sensorineural deafness, mandibular hypoplasia, hypogonadism, undescended testes, severe insulin resistance
    • References for the genes and further details of the mutations are in Supplementary Table 3.

    • C/Het, compound heterozygous; Het, heterozygous; Hom, homozygous; Hp, Hp gene deletion; Ins, insulin; OHA, oral hypoglycemic agent; tNGS, targeted next-generation sequencing.

  • Table 2

    PPV and NPV values for the biomarker pathway, traditional MODY criteria (age at diagnosis younger than 25 years, non–insulin-treated, and parent affected with diabetes), and the MODY probability calculator (using a probability >25%, the pickup rate for the diagnostic laboratory)

    NPrevalence of monogenic diabetesPPV (%)NPV (%)Percentage of monogenic cases missedNumber needed to test
    Biomarker pathway1,4073.6% (51/1,407)20.099.9105
    Traditional MODY criteria1,3623.6% (49/1,362)57.697.7632
    MODY probability calculator1,3473.3% (45/1,347)40.498.3553
    • Prevalence is the proportion of diagnosed monogenic diabetes, percentage of monogenic cases missed is the proportion of monogenic cases not picked up by the approach, and number needed to test is 1/PPV.

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Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients
Beverley M. Shields, Maggie Shepherd, Michelle Hudson, Timothy J. McDonald, Kevin Colclough, Jaime Peters, Bridget Knight, Chris Hyde, Sian Ellard, Ewan R. Pearson, Andrew T. Hattersley
Diabetes Care Aug 2017, 40 (8) 1017-1025; DOI: 10.2337/dc17-0224

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Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients
Beverley M. Shields, Maggie Shepherd, Michelle Hudson, Timothy J. McDonald, Kevin Colclough, Jaime Peters, Bridget Knight, Chris Hyde, Sian Ellard, Ewan R. Pearson, Andrew T. Hattersley
Diabetes Care Aug 2017, 40 (8) 1017-1025; DOI: 10.2337/dc17-0224
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