马凡综合征6个家系的FBN1基因变异分析  

Analysis of FBN1 gene mutations in six Chinese pedigrees affected with Marfan syndrome

作　　者：丁仙红 洪陈亮 卢扬[1,2] 徐梦忆 胡冰杰 方奕程 沈波 Ding Xianhong;Hong Chenliang;Lu Yang;Xu Mengyi;Hu Bingjie;Fang Yicheng;Shen Bo(Department of Laboratory,Taizhou Hospital of Zhejiang Province,Taizhou,Zhejiang 318000,China;Taizhou Key Laboratory of Systemic Medicine and Precision Diagnosis and Treatment,Taizhou,Zhejiang 318050,China;Department of Radiology,Taizhou Hospital of Zhejiang Province,Taizhou,Zhejiang 317000,China)

机构地区：[1]浙江省台州医院检验科,台州317000 [2]台州市系统医学与精准诊治重点实验室,台州318050 [3]浙江省台州医院放射科,台州317000

出　　处：《中华医学遗传学杂志》2025年第1期41-50,共10页Chinese Journal of Medical Genetics

摘　　要：目的探讨6个马凡综合征(MFS)家系基因变异类型及临床特征。方法选取2017—2022年于台州恩泽医疗(中心)集团就诊的6个MFS家系作为研究对象。采用回顾性研究方法,收集6个家系相关临床资料。采集6个家系先证者及其家系成员的外周血样,并提取基因组DNA;采用全外显子组测序(WES),筛查变异位点。采用Sanger测序法对6个家系先证者及家系成员的FBN1基因变异位点进行验证。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》,对检出的变异位点进行致病性评级。利用Aplha Fold3与PyMOL软件对FBN1蛋白三维结构进行同源建模,对FBN1蛋白的三维结构及氨基酸序列保守性进行分析。本研究通过了台州恩泽医疗中心(集团)医学伦理委员会的审查(伦理号:K20231002)。结果①临床特征:6个家系先证者均有心血管系统异常表现,家系2和5先证者均表现出眼部异常症状,家系1、4~6先证者均表现出骨骼系统异常症状。②基因检测结果:6个MFS家系共检测出6个FBN1基因变异位点,分别为c.1957_1958dupGT(p.Asp654fs)、c.5014T>A(p.Cys1672Ser)、c.8135delC(p.Pro2712fs)、c.2302G>T(p.Glu768*)、c.3473A>G(p.Glu1158Gly)和c.6169C>T(p.Arg2057*),涉及6个不同的外显子。③基因变异位点致病性评级结果:根据《遗传变异分类标准与指南》,4个被评级为明确致病性变异,1个被评级为可能致病性变异,1个被评级为临床意义不明确变异。c.5014T>A(p.Cys1672Ser)、c.1957_1958dupGT(p.Asp654fs)、c.8135delC(p.Pro2712fs)和c.2302G>T(p.Glu768*)4个变异位点经查阅数据库及相关文献,未见其致病的报道,确定为新变异位点。④生物信息学分析结果:SIFT和PolyPhen-2软件对c.5014T>A(p.Cys1672Ser)和c.3473A>G(p.Glu1158Gly)2个变异位点的蛋白功能预测结果均为有害性变异。通过蛋白质同源序列比对分析发现,4个新变异位点在不同物种的FBN1蛋白中高度保守。同源建模FObjectiveTo determine the types of genetic variants in six Chinese pedigrees affected with Marfan syndrome(MFS)and analyze their clinical characteristics and molecular pathogenesis.MethodsSix MFS pedigrees presented at the Taizhou Enze Medical Center(Group)between 2017 and 2022 were selected as the study subjects.Clinical data of pedigrees were retrospectively analyzed.Peripheral blood samples were collected from the probands and their family members for the extraction of genomic DNA.Whole exome sequencing(WES)was carried out.Candidate variants of the FBN1 gene were verified by Sanger sequencing.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),pathogenicity of the candidate variants was assessed.AlphaFold3 and PyMOL software were used for homology modeling of the FBN1 protein and analysis of its three-dimensional structure and amino acid sequence conservation.This study was approved by the Medical Ethics Committee of Taizhou Enze Medical Center(Group)(Ethics No.20231002).ResultsCardiovascular system abnormalities were noted in all pedigrees,ocular abnormalities were present in pedigrees 2 and 5,skeletal system abnormalities were presented in pedigrees 1,and 4 to 6.FBN1 gene mutations were identified in all pedigrees,including c.1957_1958dupGT(p.Asp654fs),c.5014T>A(p.Cys1672Ser),c.8135delC(p.Pro2712fs),c.2302G>T(p.Glu768*),c.3473A>G(p.Glu1158Gly)and c.6169C>T(p.Arg2057*),with each involving a different exon.Four variants were rated as pathogenic,one as likely pathogenic,and one as variant of uncertain significance.Among these,c.5014T>A(p.Cys1672Ser),c.1957_1958dupGT(p.Asp654fs),c.8135delC(p.Pro2712fs),and c.2302G>T(p.Glu768*)were unreported previously.Bioinformatic analysis with SIFT and PolyPhen-2 predicted that the c.5014T>A(p.Cys1672Ser)and c.3473A>G(p.Glu1158Gly)variants were deleterious.Protein homologous sequence alignment analysis revealed that the four novel mutation sites are highly conserved across various species.Homology modeling of the FBN1 protein three-dimensi

关 键 词：马凡综合征 FBN1基因 新突变 高通量测序 遗传变异 保守序列 原纤维蛋白1 

分 类 号：R71[医药卫生—妇产科学]