title: GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey.
abstract: Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.
  
  
  
  Fifty-four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99-145 mg/dl (5·5-8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation.
  
  
  
  GCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2-h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107-157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136-247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19-120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9-7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment.
  
  
  
  Approximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hysenaj
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Tulay
authors.initials: T
authors.lastname: Guran
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Saygın
authors.initials: S
authors.lastname: Abalı
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.affiliation: Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001483:Base Sequence; D001786:Blood Glucose / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D018579:Patient Selection; D018570:Risk Assessment / Q000379:methods; D014421:Turkey
chemical_list: D001786:Blood Glucose; D005941:Glucokinase; D006442:Glycated Hemoglobin