Next-gen sequencing paves way to discovery of novel forms of monogenic diabetes

Targeted next-generation sequencing (NGS) appears to be useful for pinpointing causal variants in patients with suspected monogenic diabetes (MD), broadening the spectrum of new pathogenic variants and updating knowledge of the clinical features of patients with various forms of MD, according to a recent study.

A heterogeneous group of disorders caused by mutations in a single gene, most of which regulate pancreatic β cells function, MD includes neonatal diabetes mellitus (NDM), maturity-onset diabetes in the young (MODY), and syndromic forms of diabetes such as Wolfram, Alström, and Bardet-Biedl (WABB) syndromes. [Pediatr Diabetes 2018;19:47-63]

“The development of DNA sequencing methods and the widespread use of NGS have enabled remarkable progress in the molecular diagnosis of MD. It is now estimated that monogenic forms of diabetes account for up to 5–7 percent of antibody-negative diabetes cases,” the investigators said. [Diabetologia 2017;60:625-635; J Clin Endocrinol Metab 2017;102:1826-1834; PLoS One 2019;14:e0220634]

“It should be emphasized that correct enrolment of patients and molecular diagnosis of MD is crucial for the initiation of appropriate treatment, prognosis of patients, and identification of diabetes among relatives of the patient,” they added. [Diabetologia 2010;53:2504-2508]

In the current study, the investigators used the NGS method to evaluate the genetic and clinical characteristics of 542 patients with suspected monogenic diabetes (probands) and their 142 family members (FMs). A total of 198 probands (36.5 percent) and 66 FMs (46.5 percent) were diagnosed with different forms of monogenic diabetes.

Heterozygous causative variants were detected in 11 different MD-related genes, most frequently in the GCK gene (206/264), the HNF1A gene (22/264), and the KCNJ11 gene (8/264). Among 198 positive probands, 31 pathogenic and likely pathogenic variants (15.6 percent) were assessed as novel mutations. [Diabetes Res Clin Pract 2022;doi:10.1016/j.diabres.2021.109154]

The most common types of MD diagnosed were MODY2 (GCK-MODY; 78.03 percent) and MODY3 (HNF1A-MODY; 8.33 percent). These were followed by NDM diabetes with mutations in KCNJ11 gene, MODY 5 (HNF1B-MODY), MODY 1 (HNF4A-MODY), other rare MODY diabetes forms (with variants in ABCC8, APPL1, MAFA, RFX6, WFS1 genes), MODY 4 (PDX1-MODY), and MD syndromes (Wolfram syndrome and WFS-like syndrome).

Of the 183 probands with MODY1-5 diabetes, 48.6 percent were diagnosed at the prediabetes stage, and more than half (68.7 percent) were on diet only at the time of genetic diagnosis, while 31.3 percent were additionally treated with oral hypoglycaemic drugs and/or insulin.

“An interesting observation made in our study is the presence of diabetes at the time of clinical diagnosis in just over half of the MODY patients studied (about 51 percent) and made mainly on the basis of the oral glucose tolerance test… [This suggests] that the genetic diagnosis of MODY diabetes can often be made at the stage of hyperglycaemia and therefore precede the clinical diagnosis of diabetes, further emphasizing the importance of early genetic testing,” according to the investigators.

The study was limited by the lack of both fasting and stimulated C-peptide values in all patients, which precluded identification of insulin secretion disorders. Furthermore, there were no data on body mass index values, insulin doses, and individual oral agents in all patients, which could have enriched the clinical characteristics of the patients presented.

Despite the mentioned limitations, the present data confirm the efficacy of targeted NGS method in the molecular diagnosis of patients with suspected MD, the investigators said.