Clinical and Genetic Characteristics of Patients with Early-Onset Diabetes Involving at Least Two Consecutive Generations: Whole-Exome Sequencing in Probands from 25 Pedigrees.
Chun-Qiong Ran, Ying Su, Xiong Wang, Xi Chen, Zhi-Xuan Zeng, Kun Dong, Zhe-Long Liu, Shu-Hong Hu, Yan Yang, Xue-Feng Yu, Yong Chen, Gang Yuan, Wen-Tao He
{"title":"Clinical and Genetic Characteristics of Patients with Early-Onset Diabetes Involving at Least Two Consecutive Generations: Whole-Exome Sequencing in Probands from 25 Pedigrees.","authors":"Chun-Qiong Ran, Ying Su, Xiong Wang, Xi Chen, Zhi-Xuan Zeng, Kun Dong, Zhe-Long Liu, Shu-Hong Hu, Yan Yang, Xue-Feng Yu, Yong Chen, Gang Yuan, Wen-Tao He","doi":"10.1007/s11596-025-00092-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.</p><p><strong>Methods: </strong>From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants.</p><p><strong>Results: </strong>Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands.</p><p><strong>Conclusion: </strong>Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.</p>","PeriodicalId":10820,"journal":{"name":"Current Medical Science","volume":" ","pages":"789-798"},"PeriodicalIF":1.5000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Medical Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11596-025-00092-6","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/22 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.
Methods: From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants.
Results: Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands.
Conclusion: Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.
期刊介绍：
Current Medical Science provides a forum for peer-reviewed papers in the medical sciences, to promote academic exchange between Chinese researchers and doctors and their foreign counterparts. The journal covers the subjects of biomedicine such as physiology, biochemistry, molecular biology, pharmacology, pathology and pathophysiology, etc., and clinical research, such as surgery, internal medicine, obstetrics and gynecology, pediatrics and otorhinolaryngology etc. The articles appearing in Current Medical Science are mainly in English, with a very small number of its papers in German, to pay tribute to its German founder. This journal is the only medical periodical in Western languages sponsored by an educational institution located in the central part of China.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
