Introduction
Monogenic diabetes mellitus (MDM) is a set of non-autoimmune, early-onset diabetes arising from pathogenic variant of a single causative gene.1 This disease may be inherited within families with a dominant, recessive or non-Mendelian trait or present as a spontaneous case due to a de novo variant. To date, over 40 different genetic subtypes of MDM have been identified, and each of them has a typical phenotype and a specific inheritance pattern.2 According to the pathogenic mechanism, MDM can be classified into two separate groups: genetic defects of insulin secretion and genetic defects of insulin action.2 In children, gene variants leading to β-cell loss or dysfunction are responsible for the majority of MDM cases, whereas very severe insulin resistance rarely occurs.
Although MDM is uncommon, it still accounts for 1%–6.3% of pediatric diabetes cases.3–5 The diagnosis of MDM in children with diabetes usually improves their clinical care. In neonatal diabetes mellitus (NDM), the most common MDM in childhood presenting with persistent hyperglycemia within the first 6 months of life, subcutaneous insulin was routinely used in the past. However, since 2004, numerous reports have shown that most of the patients with NDM with a pathogenic variant at the ABCC8 or KCNJ11 genes can be successfully treated with oral sulfonylureas (SUs) rather than with insulin therapy.6–8 Recent studies also demonstrated that chromosome 6-linked NDM is amenable to SU treatment.9 10 Moreover, patients with maturity-onset diabetes of the young (MODY), the most common type of MDM across all age groups and typically diagnosed before 25 years of age with an autosomal dominant inheritance, show mildly elevated blood glucose and are insulin independent.11 Monogenic insulin resistance syndrome should be treated with a combination strategy with insulin and insulin sensitizer such as thiazolidinedione.
Thus, a specific molecular diagnosis of MDM will help to predict the clinical course and guide management in a particular patient. Furthermore, it also has important implications in genetic counseling and genetic screening of other family members.
A recent study in 34 Japanese children with non-autoimmune-mediated type 1 diabetes (T1D) diagnosed at less than 5 years of age screened the INS and KCNJ11 genes by direct sequencing, and revealed four different variants of the INS gene in five cases and one variant of the KCNJ11 gene in one child.12 The study results highlight the presence of MDM in early-onset childhood diabetes.
To date, the molecular basis of MDM has not been systematically studied in Chinese patients with diabetes onset at an early age, except for some isolated NDM case reports. Lacking awareness and adequate knowledge of MDM, the majority of MDM children are initially misdiagnosed as T1D or type 2 diabetes (T2D), leading to incorrect treatment and poor prognosis.13 14 Thus, genetic testing for MDM should be performed to help clinical decision-making for diabetes care improvement.
Here, we sought to investigate the causative genes implicated in Chinese patients with MDM with onset at an early age of less than 3 years and establish an efficient strategy for genetic testing of MDM. As genetic test for at least KCNJ11, INS or ABCC8 genes is currently recommended for patients diagnosed with NDM and GCK gene for MODY, these four genes were first detected by direct sequencing. For negative cases, chromosome microarray analysis (CMA) was performed to identify chromosome abnormalities, and whole exome sequencing (WES) was conducted to enable the simultaneous analysis of multiple genes, including the candidate causative genes of MDM.7 15