title: Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.
abstract: Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.|National Institute for Health Research, Exeter Clinical Research Facility, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: K A
authors.initials: KA
authors.lastname: Patel
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.|National Institute for Health Research, Exeter Clinical Research Facility, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Oram
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: E
authors.initials: E
authors.lastname: De Franco
authors.affiliation: Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: K
authors.initials: K
authors.lastname: Colclough
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.|National Institute for Health Research, Exeter Clinical Research Facility, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: M
authors.initials: M
authors.lastname: Shepherd
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.|Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: M N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK.|National Institute for Health Research, Exeter Clinical Research Facility, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D055815:Young Adult