Ran Chun-Qiong, Su Ying, Wang Xiong, Chen Xi, Zeng Zhi-Xuan, Dong Kun, Liu Zhe-Long, Hu Shu-Hong, Yang Yan, Yu Xue-Feng, Chen Yong, Yuan Gang, He Wen-Tao
Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Clinical Medical Research Center for Endocrinology and Metabolic Diseases, Wuhan, 430030, China.
Curr Med Sci. 2025 Jul 22. doi: 10.1007/s11596-025-00092-6.
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.
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.
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.
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.
早发型多代糖尿病的分子机制尚不清楚。本研究旨在调查至少连续两代患早发型糖尿病的临床和遗传特征。
从1296例糖尿病住院患者中，我们选取年龄≤30岁且临床怀疑患有家族性单基因糖尿病的个体。收集先证者及其家庭成员的临床资料。采用全外显子组测序（WES）来识别可能导致糖尿病的变异。候选致病变异通过桑格测序进行验证，评估其在家庭成员中的共分离情况，并根据美国医学遗传学与基因组学学会以及分子病理学协会（ACMG/AMP）指南进行评估。此外，错义变异和同义变异通过MutationTaster和PolyPhen-2进行计算机致病性预测。使用RNAfold预测同义变异的RNA结构改变。
纳入了25例有家族糖尿病史的早发型糖尿病患者。在4例患者中检测到致病变异/可能的致病变异（HNF1A基因中的p.Gly292fs、PDX1基因中的p.Gly245Argfs*22、KCNJ11基因中的p.Asp329His、WFS1基因中的p.Leu734Phe和p.Val606Gly），根据基因检测结果对这些患者进行了准确诊断并给予合理的降糖药物治疗。在3例先证者中鉴定出意义未明的变异（ABCC8基因的c.3039 G＞A（p.Ser1013 = Ser）、MAPK8IP1基因的p.Gln144_Gly145insSerGln以及TBC1D4基因的p.Arg1249Trp）。
至少连续两代患早发型糖尿病的患者可能携带遗传变异。对该人群进行基因检测可实现精准诊断，为个体化治疗提供依据，并便于进行遗传咨询。
