2400-P: Genetic and Clinical Characteristics of HNF4A-MODY in Chinese Early Onset Diabetes Mellitus

Introduction and Objective: Maturity-onset diabetes of the young due to variants of hepatocyte nuclear factor 4-α (HNF4A-MODY) is rare and has not been well studied in Chinese early onset diabetes (EOD). This study aimed to estimate its prevalence in Chinese EOD and elucidate the clinical and genetic characteristics. Methods: Among 679 patients with EOD, high-throughput sequencing was used to screen the variants of HNF4A. The identified variants were then validated using Sanger sequencing, and the pathogenicity was evaluated according to the American College of Medical Genetics and Genomics guidelines. Results: Among 679 patients with EOD, 12 probands (1.8%) with HNF4A-MODY were identified, carrying 8 rare variants: p.V404I, p.G209R, p.R331C, p.Q360X, p.A395T, p.I441V, p.A454T, and p.P450L. All were unreported novel variants and classified as pathogenic/likely pathogenic (P/LP) according to ACMG criteria. One was a nonsense variant, while the others were missense variants. The average age of patients was 33.5 ± 10.7 years, with a mean diagnosis age of 22.7 ± 6.4 years. Mean BMI was 27.7 ± 3.7 kg/m², FPG 7.6 ± 3.1 mmol/L, HbA1c 8.6 ± 2.0%, fasting insulin level 12.4 (9.1, 26.7) μU/ml. 75.0% of patients were overweight or obese. Diabetic nephropathy occurred in 3 (25.0%) patients, and 1 patient had comorbid coronary heart disease. Conclusion: The prevalence of HNF4A-MODY is 1.8% among EOD, with 25.0% developing diabetic nephropathy. It is associated with a higher risk of diabetic nephropathy. Conducting genetic testing for EOD is of great importance for personalized diagnosis and treatment, as well as for the prevention and management of complications. Disclosure M. Li: None. X. Han: None. L. Zhou: None. L. Ji: None. Funding The 2024 National Clinical Key Specialty Construction Program of China (Department of Endocrinology, Peking University People's Hospital) with support from the central government budget