Molecular diagnosis of maturity‐onset diabetes of the young in a cohort of Chinese children

Abstract

Objective: The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China. Methods: Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES. Results: Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels. Conclusions: Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations. K E Y W O R D S childhood, maturity-onset diabetes of the young, South China, whole-exome sequencing Aijing Xu and Yunting Lin contribute equally to this work.

Clinical and genetic features of maturity-onset diabetes of the young in pediatric patients: a 12-year monocentric experience

“…Finally, due to the technology used for genetic investigations, some gene variations characterized by large gene deletions may have been overlooked. This group of large genomic rearrangements, including 17q12 microdeletions, have been described in literature as responsible for the majority of cases of HNF1B-MODY, known as MODY 5 [46,47]…”

Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population

“…The study on Russian children with non-type 1 diabetes showed that the most prevalent MODY type was GCK, with only 18% of variants in other than known MODY genes. The studies from China reported that HNF4A MODY types were relatively less common as compared to Europeans[ 18 , 19 ]. A study from Korea also has a similar finding that common MODY types prevalent in Europe were not common there, but instead they found variants in three new genes, including the WFS1 gene[ 20 ].…”

Pediatric diabetes in China: Challenges and actions

“…Second, monogenic diabetes, especially Maturity onset diabetes of the young (MODY), is an emerging type of diabetes lately in Chinese children and adolescents, which was commonly misdiagonised. 2 Third, pediatric diabetes is a lifelong disease with multiple tricky complications. Diabetic ketoacidosis (DKA) is the most serious cause of death in pediatric diabetes.…”