Maturity onset diabetes of the young (MODY) in Chinese children: genes and clinical phenotypes

Abstract

Background To investigate the clinical and molecular characteristics of Chinese children with maturity onset diabetes of the young (MODY). Methods A total of 42 Chinese patients suspected MODY referred to our unit from 2014 to 2018 were enrolled. Mutational analysis of monogenic diabetes mellitus genes was performed by next-generation sequencing and confirmed by Sanger sequencing. Results There were 28 males (66.7%) and 14 females (33.3%) with a mean age of 9.49 ± 3.46 years (range, 1.4–15.3 years) and a mean birth weight of 3.38 ± 0.49 kg (range, 2.55–4.90 kg). Among these patients, 15 patients had polyuria, polydipsia or weight loss. Two patients (4.8%) were obese and six (14.3%) were overweight. Moreover, 13 patients (30.9%) had a family history of diabetes. Thirty variants were identified in 28 patients. Twenty-six variants in 25 patients were pathogenic or likely pathogenic genes (59.5%, 25/42), including 15 patients (60.0%, 15/25) with GCK mutation, four (16.0%, 4/25) with PAX4 mutation, three (12.0%, 3/25) with HNF4A mutation, one (4.0%, 1/25) with INS mutation, one (4.0%, 1/25) with NEUROD1 mutation and one (4.0%, 1/25) with HNF1A mutation. Nine mutations (36.0%, 9/25) were novel. There was no difference between mutation-suspected patients and MODY-confirmed patients except for a 2-h glucose increment in an oral glucose tolerance test (OGTT), while the GCK-MODY had lower glycated hemoglobin (HbA1c) and a significantly smaller 2-h glucose increment in an OGTT compared with transcription factor MODYs. The GCK-MODY was identified by incidental hyperglycemia without glycosuria. GCK-MODY without drug management and hepatocyte nuclear factor-1 alpha (HNF4A) or HNF1A-MODY with sulfonylurea therapy obtained good glucose controlling. Conclusions Mutation of the GCK gene is the most common in MODY patients in China followed by PAX4. The screening criteria can improve the cost-effectiveness of disease diagnosis and treatment. A precise molecular diagnosis would lead to optimal treatment of the patients.

Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia

“…HNF1A-MODY even accounts for 52% of all MODY in the UK 7 . The detection rate of HNF1A-MODY was 14.3% (1/7 MODY patients) in the present cohort, which was higher than that of another Chinese study (1/28 MODY patients) 12 ; however, it was lower than that reported by a Korean study (3/14 MODY patients) 13 . Therefore, HNF1A-MODY appears to be uncommon in Chinese cohorts of children and adolescents with diabetes/persistent hyperglycemia.…”

“…Another study identified 25 out of 42 Chinese patients with suspected MODY as having pathogenic or likely pathogenic variants, and 15 patients (60.0%, 15/25) with a GCK mutation, which is consistent with a Korean report (50.0%, 7/14). However, the Chinese study reported 36.0% of the mutations as novel, suggesting a unique mutation distribution in China 12,13 . As the rate and type of genetic mutations, as well as the presence of uncharacteristic clinical features associated with diabetes/persistent hyperglycemia, vary among different populations, it is necessary to define the genetic etiology associated with diabetes in children and adolescents in China further.…”

Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes

“…Application of the widely used American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) standards and guidelines (5) classifies only nine of these 88 variants as likely pathogenic or pathogenic variants that would be reported by our clinical diagnostic laboratory as likely causative of the patients' diabetes. This is not an isolated occurrence; other published research studies with an overreliance on in silico prediction tools have reported high levels (~90%) of false positive "likely pathogenic" monogenic diabetes variants (1)(2)(3). We have seen clinical diagnostic reports from laboratories in eight coun-tries across Europe, Asia, the Middle East, and the United States that have similarly reported such variants as incorrectly likely causative of a patient's diabetes.…”

“…Recently published examples involving monogenic diabetes demonstrate how pathogenicity prediction algorithms can be very inaccurate for predicting which genetic variants are likely causal of dominant monogenic disease (1)(2)(3)(4). Here, we highlight the potential pitfalls of variant classification and how they can be avoided.…”

Molecular genetic study in a cohort of Iranian families suspected to maturity-onset diabetes of the young, reveals a recurrent mutation and a high-risk variant in the CEL gene

“…The most common types of MODY were reported as MODY2 and MODY3 in many studies in populations other than Iran. [ 38 ] However, there are few studies on MODY to provide data concerning the frequency of different types of MODY in Iran. Moghbeli et al , in 2017 reported that among 34 Iranian families of MODY patients, only 2% of them harbored mutations in HNF1A gene.…”