Publication: GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey
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Date
2016-09
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WILEY-BLACKWELL
Abstract
ObjectiveInactivating 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 PatientsFifty-four unrelated probands were selected based on the following criteria: age of diagnosis 17years, 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 (05U/kg/d). A MODY probability score () was calculated and 21 patients with a score 75%, HbA1c levels 75% (585mmol/mol) and fasting blood glucose (FBG) levels 99-145mg/dl (55-80mmol/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. ResultsGCK 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 12314mg/dl (68 +/- 07mmol/l) (107-157mg/dl) and 181 +/- 30mg/dl (101 +/- 16mmol/l) (136-247mg/dl), respectively. Average of glucose increment in OGTT was 58 +/- 27mg/dl (32 +/- 15mmol/l) (19-120mg/dl), and mean HbA1c level was 65 +/- 05% (475 +/- 55mmol/mol) (59-76%). 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. ConclusionsApproximately 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.
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Keywords
GLUCOKINASE MUTATIONS, PREVALENCE, CHILDREN, MELLITUS, DIAGNOSIS, FAMILIES, CAMPAIGN, COHORT