The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association.

Introduction: Gestational diabetes mellitus (GDM), the most common metabolic complication of pregnancy, is associated with a 50% increase in subsequent risk for type 2 diabetes. There is increasing interest in identifying biomarkers that may facilitate the stratification of subsequent type 2 diabetes risk among women with GDM. In this study, we considered the choline acetyltransferase (ChAT) gene. CHAT plays a critical role in acetylcholine synthesis and regulates insulin secretion from the pancreatic islet to maintain glucose homeostasis.

Methods: We screened for deleterious variants in the ChAT gene in 12 GDM patients and 10 ethnically matched controls from a South African cohort. We isolated DNA from the placental samples of these patients and performed DNA sequencing of the protein-coding region of the ChAT gene. Sequence alignments and variant annotations were done using UGENE software and Ensembl VEP.

Results: A novel heterozygous missense variant in exon 8 of the ChAT gene was identified. The plausible phenotypic impact of the variant ChAT (NM_020549.5):c.1213C>G (p.Leu405Val) can be explained by haploinsufficiency, changing protein activities, strong transcription activity, and epigenetic repression activities of the variant. Also, structurally, the variant is located 18bp in-frame to a stop-gained variant (p.Gly411Ter). The RegulomeDB DNase expression data clearly show the identified variant in a peak expression in the spleen and placenta. This observation corroborates that the ChAT gene may play an essential role in GDM.

Conclusion: Taken together, the metric scores for this variant show that it could affect the functions of the gene, but more functional studies are necessary to validate these effects. Consequently, this study sets the stage for the future screening of a larger cohort and functional validation of deleterious variants to underpin the ChAT gene and GDM association.