Molecular diagnosis of maturity-onset diabetes of the young via whole-exome sequencing: a cohort study in Taizhou, China.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a monogenic disease that is often undiagnosed or misdiagnosed in China, leading to inappropriate therapy. In this study, we aimed to determine the pathogenic variants in Chinese patients with clinically suspected MODY. METHODS: A total of 20 probands from 20 unrelated families with suspected MODY in Taizhou Hospital affiliated to Wenzhou Medical University from 2019 to 2023 were enrolled. Whole-exome sequencing (WES) and WES-based copy number variant (CNV) detection were performed for mutational analysis, and the genotype and phenotype of these affected patients were analyzed. RESULTS: In this cohort, there were 12 males (60.0%) and 8 females (40.0%) with a mean age of 16.2 ± 5.9 years (range 4.8–27.0 years) and a mean age of diabetes diagnosis of 14.9 ± 5.6 years (range 4.0–24.0 years). Among these patients, 13 patients experienced polyuria, polydipsia or weight loss, and 8 patients showed additional features such as hyperuricemia, uterine malformation and renal cysts. Genetic analysis identified 5 pathogenic mutations of 2 MODY genes in 5 families, accounting for 25% of potential families. Three patients (15.0%, 3/20) harbored HNF1A variants, while two cases (10.0%, 2/20) carried whole HNF1B deletion. No significant difference in clinical characteristics except for fasting insulin levels were found between MODY patients and non-MODY patients. Following an accurate genetic diagnosis, two probands with MODY3 and their affected parents achieved good glycemic control after switching to sulfonylureas. CONCLUSION: Using the WES technology, pathogenic variants in the HNF1A and HNF1B genes were detected in 5 (25.0%) families of the Taizhou cohort in China. Our study underscores the importance of precise molecular diagnosis for optimal treatment and management of patients and helps to enhance the clinicians’ awareness of the disease and reduce the misdiagnosis of MODY.