GCK gene mutations are a common cause of childhood‐onset MODY (maturity‐onset diabetes of the young) in Turkey

Summary Objective 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. Design and Patients 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. Results 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. Conclusions 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.