Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes.
Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing.



We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide-positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes.



A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6-3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients).



This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. m.h.shepherd@exeter.ac.uk.|Exeter National Institute for Health Research Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Maggie
M
Shepherd
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Beverley
B
Shields
Exeter National Institute for Health Research Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Suzanne
S
Hammersley
Exeter National Institute for Health Research Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Michelle
M
Hudson
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.|Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Timothy J
TJ
McDonald
Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Kevin
K
Colclough
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Richard A
RA
Oram
Exeter National Institute for Health Research Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Bridget
B
Knight
Exeter Test Group, Institute of Health Research, University of Exeter Medical School, Exeter, U.K.
Christopher
C
Hyde
Department of Paediatrics, Northern Devon Healthcare NHS Trust, Barnstaple, U.K.
Julian
J
Cox
Department of Paediatrics, Royal Cornwall Hospitals NHS Trust, Truro, U.K.
Katherine
K
Mallam
Department of Paediatrics, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K.
Christopher
C
Moudiotis
Children & Young People's Outpatient Department, Plymouth Hospitals NHS Trust, Plymouth, U.K.
Rebecca
R
Smith
Department of Paediatrics, South Devon Healthcare NHS Foundation Trust, Torquay, U.K.
Barbara
B
Fraser
Department of Paediatrics, Royal Cornwall Hospitals NHS Trust, Truro, U.K.
Simon
S
Robertson
Child Health, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, Scotland, U.K.
Stephen
S
Greene
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Sian
S
Ellard
Division of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Dundee, U.K.
Ewan R
ER
Pearson
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Andrew T
AT
Hattersley
D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology; D015415:Biomarkers; D002096:C-Peptide / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D003937:Diagnosis, Differential; D004739:England / Q000453:epidemiology; D005260:Female; D005820:Genetic Testing; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D012606:Scotland / Q000453:epidemiology; D017422:Sequence Analysis, DNA; D064233:Sulfonylurea Receptors / Q000235:genetics; D055815:Young Adult
C577507:ABCC8 protein, human; D015703:Antigens, CD; D001323:Autoantibodies; D015415:Biomarkers; D002096:C-Peptide; D000081410:Germinal Center Kinases; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D064233:Sulfonylurea Receptors; D051539:Hepatocyte Nuclear Factor 1-beta; C435941:INSR protein, human; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases