Novel phenotype due to KCNJ11 pathogenic variant associated with maturity-onset diabetes of the young-KCNJ-11

Introduction: Maturity-onset diabetes of the young (MODY) KCNJ11 is caused by pathogenic variants in the KATP channel of the pancreatic beta-cell leading to altered insulin secretion. Bi-allelic loss-of-function variants lead to neonatal diabetes mellitus (DM) whereas heterozygous gain-of-function variants lead to congenital hyperinsulinism. Heterozygous loss-of-function variants, however, are suggested to cause a bimodal pattern with hyperinsulinaemic hypoglycaemia in early life (with an often-mild presentation) and progressing to glucose intolerance in early adulthood. Case description: We describe three family members with early-onset DM (or glucose intolerance) without clear features of type 1 or type 2 DM. A heterozygous likely pathogenic missense variant c.119G>A (p.(Gly40Asp)) was found in an autosomal dominant pattern. This variant was previously only linked to cases of congenital hyperinsulinism and had been described as likely pathogenic or pathogenic in patients with type 2 DM. Conclusion: To our knowledge, this is the first report linking the c.119G>A KCNJ11 variant to a clinical context of MODY. We have no evidence in our patients of clinically significant hypoglycaemia at young age. However, we still hypothesise - congruent with the latest evidence - that there might be a bimodal pattern in individuals with this variant. This report adds to the clinical and genetic heterogenicity of MODY and illustrates the complexity of early diagnosis of MODY.