Diabetes Metab J.  2025 Mar;49(2):321-330. 10.4093/dmj.2024.0159.

Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes

• Gong S
• Lian H
• Li Y
• Cai X
• Liu W
• Luo Y
• Li M
• Zhang Sm
• Zhang R
• Zhou L
• Zhu Y
• Ren Q
• Zhang X
• Chen J
• Wu J
• Zhou X
• Wang X
• Han X
• Ji L

• KMID: 2565354
• DOI: http://doi.org/10.4093/dmj.2024.0159

Abstract

Background
Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients.
Methods
Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines.
Results
Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher.
Conclusion
MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Keyword

Diabetes mellitus; Diabetes mellitus, type 2; Genetics, medical; Maturity onset diabetes of the young, type 5; Prevalence

Figure

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  Fig. 1. Dual-luciferase reporter assay of constitutive hepatocyte nuclear factor 1-beta (HNF1β) variants. (A) Detection of transcriptional activity of different variants of HNF1β using glucose transporter 2 (GLUT2) as the promoter. (B) Detection of transcriptional activity of different variants of HNF1β using insulin (INS) as the promoter. Following the procedures outlined in the methods section, 293T cells were transfected with expression vectors containing both wild-type of HNF1β, rare variants of HNF1β screened out in this study, and the INS or GLUT2 reporter plasmid. The luciferase activity was measured relative to the GLUT2-pcDNA3.1 or INS-pcDNA3.1 control group. S148W variants is a loss-of-function mutation in HNF1β gene reported before, serving as a positive control in this assay. aP<0.05, bP<0.01, cP<0.001.

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