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

Abstract

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.

Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis

“…To our knowledge, WES has been widely used in clinical and genomic research; however, only one study has used this method to identify genetic variants in GDM cases. A recent study by Nikolai Paul et al screened 50 non-obese GDM Maltese women, and identified three pathogenic variants, rs201815564, rs37046485, and rs766191969, in the ABCC8 , GCK , and HNF1A genes, respectively [ 97 ]. Additionally, subjects with these variants reported interrupted fasting glucose levels several times [ 97 ].…”

“…A recent study by Nikolai Paul et al screened 50 non-obese GDM Maltese women, and identified three pathogenic variants, rs201815564, rs37046485, and rs766191969, in the ABCC8 , GCK , and HNF1A genes, respectively [ 97 ]. Additionally, subjects with these variants reported interrupted fasting glucose levels several times [ 97 ]. Nevertheless, replication of these studies is needed considering the limited number of subjects, the ethnic heterogeneity of the Maltese population, and the possibility of variants in intronic regions not covered by WES [ 97 ].…”

“…Additionally, subjects with these variants reported interrupted fasting glucose levels several times [ 97 ]. Nevertheless, replication of these studies is needed considering the limited number of subjects, the ethnic heterogeneity of the Maltese population, and the possibility of variants in intronic regions not covered by WES [ 97 ].…”

The Maleth program: Malta's first space mission discoveries on the microbiome of diabetic foot ulcers

“…Coincidentally in 2019, Malta had the highest recorded obesity rates, in both sexes, amongst the EU countries. Obesity is one of the predisposing factors of diabetes and this together with various genetic mutations identified in the Maltese population contribute to the high prevalence of diabetes in Malta (Eurostat, 2021; Cuschieri et al., 2016 ; Pace et al., 2019 , 2021 ). As diabetic patients are at risk of ischaemia, peripheral neuropathy and an impaired immunity, 12–25% are at a high risk of developing diabetic foot ulcers (DFUs).…”