Genetic and Clinical Characterization of Patients with Maturity-Onset of Diabetes of the Young (MODY): Identification of Novel Variations

Abstract

Background: Maturity-onset diabetes of the young (MODY) is a rare monogenic type of diabetes, and accounts for 2-5% of all diabetes cases. An early age of onset, a family history supporting autosomal-dominant inheritance, insulin resistance, and the absence of autoimmunity are the major characteristics of MODY. However, genetic testing is crucial for diagnosis. Aims: To investigate the 7 MODY-related genes and clinical findings of patients with a preliminary clinical diagnosis of MODY. Study Design: Retrospective cross-sectional study. Methods: In this study, 7 genes ( KCNJ11, ABCC8, INS, GCK, HNF4A, HNF1A, and HNF1B ) related to MODY were screened via targeted sequencing in 182 cases with a confirmed pre-diagnosis of MODY. The clinical characteristics of the patients were evaluated retrospectively. Results: A total of 182 patients, 48% of whom were women, between the ages of 18-62 were included in the study. In 30 cases (16.4%), 28 different pathogenic variations were found, of which 20 were previously reported and 8 were novel variations segregated by disease within the family. Pathogenic variations were detected in the following genes in order of mutation frequency; GCK, HNF1A, ABCC8, HNF4A, HNF1B and KCNJ11 . Interestingly, six of the 30 cases (20%) carried a pathogenic variation in the ABCC8 gene. No mutation was detected in the INS gene. A family history of vertically transmitted diabetes and elevated HbA1C at the time of diagnosis were found in 20 (66%) and 16 (52%) cases, respectively. Conclusion: In this series, 28 different pathogenic variations are ­identified, 8 of which are novel. The rate of pathogenic variation in the ABCC8 gene is unexpectedly high. Two-thirds of cases have a family history of vertically transmitted diabetes.

A synonymous variant in KCNJ11 leading to MODY13: a case report and literature review

“…Diabetes mellitus prevailed in 60% of the patients' families. Aside from blood glucose, there were no signi cant differences in MODY13 patients' sex, ethnicity, blood pressure, C-peptide, FT4, or insulin-related antibodies when versus KCNJ11 mutation-associated neonatal diabetes mellitus 16,[23][24][25] .…”

Expanding the mutational spectrum ofGCKin Turkish pediatric population

“…Several Turkish patient series of GCK-MODY have been published previously, which figure out an approximate landscape of the GCK variants in the Turkish population (Agladioglu et al, 2016; Altan et al, 2020; Anik et al, 2015; Ates et al, 2021; Aykut et al, 2018; Bolu, Eroz, Dogan, Arslanoglu, & Dundar, 2020; Dundar, 2023; Duzkale & Emiroglu, 2023; Haliloglu et al, 2016; İşleyen & Semih, 2019; Ozdemir et al, 2018; Sağsak, Önder, Kendirci, Yıldız, & Doğan, 2022; Siklar & Berberoglu, 2016; Yalcintepe et al, 2021; Yilmaz Uzman et al, 2022). Still, only 58% of the variants detected in our patients overlapped with those in the previous series of the Turkish population.…”

A synonymous KCNJ11 variant leading to MODY13: A case report and literature review

“…Diabetes family history is described in 60% of the patients' families. Aside from blood glucose and genetic characteristics, there were no significant differences between MODY13 patients' sex, ethnicity, blood pressure, C-peptide, FT4, or insulin-related antibodies versus KCNJ11 -associated neonatal diabetes mellitus [ 16 , [23] , [24] , [25] ]. In our study, the “separation phenomenon” between C-peptide and insulin in standard meal tests is first described, which we hypothesized to be in relation to patients harboring the homozygous mutation that had been reported in a CHI patient.…”