Clinical phenotype and genetic analysis of MODY3 caused by the HNF1A-c.47T>A variant
10.3760/cma.j.cn311282-20250429-00225
- VernacularTitle:HNF1A-c.47T>A变异致MODY3临床表型及遗传学分析
- Author:
Zhenjing WANG
1
;
Caihui QI
;
Mingzhong TIAN
;
Xin LIU
;
Xin LI
;
Chao XU
;
Shuping WANG
Author Information
1. 东营市人民医院（山东省立集团东营医院）内分泌科，东营 257091
- Publication Type:Journal Article
- Keywords:
Maturity-onset diabetes of the young type 3(MODY3);
HNF1A;
Dimerization domain
- From:
Chinese Journal of Endocrinology and Metabolism
2025;41(8):643-648
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the clinical characteristics of a family with maturity-onset diabetes of the young type 3(MODY3) and assess its association with the novel HNF1A-c.47T>A variant.Methods:A genetic pedigree of the MODY3 family was constructed, and clinical data were collected. Whole-exome sequencing combined with Sanger sequencing was used, followed for familial co-segregation analysis. Bioinformatics tools, including multiple sequence alignment–based conservation analysis and protein structural prediction, were conducted to validate the association between the novel HNF1A-c.47T>A variant and MODY3.Results:Seven MODY3 patients were diagnosed in this family, all harboring the HNF1A-c.47T>A heterozygous variant. AlphaFold2 protein structure prediction indicated that the HNF1A-c.47T>A variant altered the conformation of the first pair of α-helices within the protein dimerization domain.Conclusion:Based on co-segregation analysis, sequence conservation assessment, protein structure prediction, and classification based on American College of Medical Genetics and Genomics(ACMG) Guidelines, the HNF1A-c.47T>A variant was determined to be pathogenic for MODY3. This study reports this novel pathogenic variant, expanding the mutational spectrum of MODY3. By revealing its disruptive effect on the protein dimerization domain, the findings provide a potential molecular basis for the diagnosis and management of patients carrying similar variants.
