摘要
目的评估中国早发青少年糖尿病队列中单基因糖尿病(monogenic diabetes,MgD)诊断率,重点分析综合征相关基因(WFS1、INSR、HNF1B与MT-TL1 m.3243A>G)的变异谱与临床表型特征。方法纳入2021年至2024年于上海交通大学医学院附属瑞金医院就诊的早发青少年糖尿病患者208例,采集外周血进行全外显子组测序。可疑变异经Sanger验证并依据美国医学遗传学与基因组学学会指南分级。整合文献中WFS1相关病例数据,系统比较其等位基因构型与尿崩症(diabetes insipidus,DI)、视神经萎缩(optic atrophy,OA)、感觉神经性耳聋(sensorineural deafness,D)的发生率。结果共31例(14.90%)检出致病/可能致病变异,涉及12个基因;其中35.48%(11/31)为综合征相关基因(WFS16例、INSR 3例、HNF1B 1例和线粒体m.3243A>G 1例)。WFS1跨队列分析显示,国内队列以复合杂合与单一杂合为主,双等位频率(55.56%)显著低于国外队列(94.44%);国内OA与D发生率也更低(均q<0.001)。INSR相关病例呈现表型异质性,部分缺乏典型皮肤体征;HNF1B与线粒体病例分别表现为多系统受累及母系遗传特征。结论在中国早发青少年糖尿病人群中,综合征相关MgD占有重要比例,遗传构型以单/复合杂合为主且表型隐匿,仅依赖经典综合征表型易导致漏诊。建议对所有早发糖尿病患者实施分层遗传检测(涵盖WFS1、INSR、HNF1B及线粒体基因),并对确诊者进行长期随访。
Objective To assess the diagnostic yield of monogenic diabetes(MgD)in a Chinese cohort of early-onset,youth-onset diabetes,and to characterize the variant spectrum and clinical phenotypes associated with syndromic genes(WFS1,INSR,HNF1B,and mitochondrial MT-TL1 m.3243A>G).MethodsA total of 208 patients with early-onset youth-onset diabetes who presented to Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,between 2021 and 2024 were enrolled.Whole-exome sequencing was performed on peripheral blood samples,with candidate variants validated by Sanger sequencing and classified according to American College of Medical Genetics and Genomics(ACMG)criteria.Published WFS1-related cases were additionally reviewed to compare allele configurations and the prevalences of central diabetes insipidus(DI),optic atrophy(OA),and sensorineural deafness(D).ResultsPathogenic or likely pathogenic variants were identified in 31/208 patients(14.90%)across 12 genes;of which 35.48%(11/31)involved syndromic genes(WFS1,n=6;INSR,n=3;HNF1B,n=1;mitochondrial m.3243A>G,n=1).Cross-cohort analysis of WFS1 showed that the Chinese cohort was enriched for compound-heterozygous and monoallelic variants,with a significantly lower frequency of biallelic genotypes compared with international cohorts(55.56%vs 94.44%);the prevalences of OA and D were likewise significantly lower(both q<0.001).INSR-related cases exhibited substantial phenotypic heterogeneity,with some lacking classic dermatologic features;HNF1B-related cases exhibited multisystem involvement,whereas mitochondrial cases showed maternal inheritance.ConclusionsSyndromic MgD represents a notable proportion of early-onset youth-onset diabetes in China.Genotypes are predominantly monoallelic or compound-heterozygous,often accompanied by subtle or incomplete syndromic presentations,making diagnosis based solely on classic features unreliable.Comprehensive tiered genetic testing—incorporating WFS1,INSR,HNF1B,and mitochondrial loci—is recommended for all early-onset diabetes patients,alongside long-term follow-up for confirmed carriers.
作者
盛羽轩
吴磊
张娟
李丹洁
章钟允
韩如来
张翼飞
王卫庆
宁光
叶蕾
顾卫琼
Sheng Yuxuan;Wu Lei;Zhang Juan;Li Danjie;Zhang Zhongyun;Han Rulai;Zhang Yifei;Wang Weiqing;Ning Guang;Ye Lei;Gu Weiqiong(Department of Endocrine and Metabolic Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China)
出处
《中华内分泌代谢杂志》
2026年第1期28-37,共10页
Chinese Journal of Endocrinology and Metabolism
基金
四大慢病重大专项(2025ZDO549402)
国家重点研发计划(2023YFC2506001)
国家自然科学基金(82470886)
申康诊疗技术推广及优化管理项目(SHDC22024243)。
