High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus

Abstract

Context:Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of β-cell dysfunction.Objectives:We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up.Design, Setting, and Patients:We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow-up 10 years after the index pregnancy.Main Outcome Measures:The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured.Results:At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS.Conclusions:Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM.

Screening for monogenic diabetes in primary care

“…Their knowledge regarding the social and family history of the patient can facilitate transferring from insulin to sulphonylureas, thus promoting better quality of life in different ways. [37,38] • Patients taking insulin for years may experience uncertainty, fear, anxiety and excitement on changing to tablets. • Changing from a routine of 2-4 insulin injections a day to tablet therapy improves lifestyle and self-image.…”

“…Gjesing et al diagnosed 5-6% of women with GDM with GCK MODY. Furthermore, 6% of diet treated GDM Danish women were identified as having possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B or INS [38]. These women are at high risk of developing diabetes after pregnancy, and the authors recommended that screening for mutations in these genes should be offered to women with GDM.…”

GCKGene Screening and Association ofGCKVariants With Gestational Diabetes in North Indian Population

“…Gjesing et al 9 reported a combined GCK, HNF1A, HNF4A, HNF1B , and INS variant prevalence of 5.9% in Danish women with GDM. We calculated the minimum required sample sizeas 15 using OpenEpi software version 3.01, with 95% confidence level, 5% precision and 80% power.…”

“… 7 , 8 A recent study conducted in Denmark reported a 5.8% prevalence of variants of GCK, HNF1A, HNF4A, HNF1B , or INS among women diagnosed with GDM. 9 Heterozygous mutations in the GCK gene have also been reported to be a cause of a subtype of maturity-onset diabetes of the young (MODY), GCK-MODY or MODY 2. 10 Data on the link between GDM and GCK gene is scarce in the Indian perspective.…”

Mutations in transcription factor as rare causes of diabetes in pregnancy

“…В исследовании Weng [6] в 1% случаев (n=66) выявлены мутации в гене HNF1A, а в работе Gjesing A. и соавт. мутации в генах HNF4A и HNF1A обнаружены в 3,7% случаев (13/354) [7]. До настоящего времени в отечественной литературе не описано течение диабета беременных, обусловленного мутациями в генах ядерных факторов гепатоцитов, в связи с чем мы приводим описание 7 клинических случаев неиммунного сахарного диабета типов MODY1 и MODY3.…”