Frequency and spectrum of glucokinase mutations in an adult Maltese population.

AIM: To investigate the frequency and spectrum of glucokinase (GCK) mutations in a cohort of adults from an island population having a high prevalence of diabetes mellitus (DM). METHODS: A single-centre cohort study was conducted, including 145 non-obese adults of Maltese-Caucasian ethnicity with impaired fasting glycaemia (IFG) or non-autoimmune diabetes diagnosed before the age of 40 years. Bidirectional sequencing of the GCK coding regions was performed. Genotype-phenotype associations and familial segregation were explored and the effects of missense variants on protein structure were evaluated using computational analysis. RESULTS: Three probands with pathogenic/likely pathogenic GCK variants in the heterozygous state having clinical features consistent with GCK-diabetes were detected. The missense variants have structurally destabilising effects on protein structure. GCK variant carriers exhibited a significantly lower body mass index and serum triglyceride levels when compared to GCK variant non-carriers. CONCLUSIONS: The frequency of GCK-diabetes is approximately 2% in non-obese Maltese adults with diabetes or prediabetes. This study broadens the mutational spectrum of GCK and highlights clinical features that could be useful in discriminating GCK-DM from type 2 DM or prediabetes. It reinforces the need for increased molecular testing in young adults with diabetes having a suspected monogenic aetiology.

Screening for monogenic subtypes of gestational diabetes in a high prevalence island population - A whole exome sequencing study.

AIMS: The reported frequency of monogenic defects of beta cell function in gestational diabetes (GDM) varies extensively. This study aimed to evaluate the frequency and molecular spectrum of variants in genes associated with monogenic/atypical diabetes in non-obese females of Maltese ethnicity with GDM. METHODS: 50 non-obese females who met the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for diagnosis of GDM and with a first-degree relative with non-autoimmune diabetes were included in this study. Whole exome capture and high throughput sequencing was carried out. Rare sequence variants were filtered, annotated, and prioritised according to the American College for Medical Genetics guidelines. For selected missense variants we explored effects on protein stability and structure through in-silico tools. RESULTS: We identified three pathogenic variants in GCK, ABCC8 and HNF1A and several variants of uncertain significance in the cohort. Genotype-phenotype correlations and post-pregnancy follow-up data are described. CONCLUSIONS: This study provides the first insight into an underlying monogenic aetiology in non-obese females with GDM from an island population having a high prevalence of diabetes. It suggests that monogenic variants constitute an underestimated cause of diabetes detected in pregnancy, and that careful evaluation of GDM probands to identify monogenic disease subtypes is indicated.