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FBN1蛋白三维结构，并比对分析发现， FBN1基因6个变异位点在氨基酸附近氢键及蛋白质二维、三维结构等发生了不同程度改变，验证了 FBN1基因变异与MFS之间的关系。 结论:本研究共发现了4个 FBN1基因新变异位点，进一步拓展了MFS的变异谱和表型谱，为遗传咨询和疾病诊疗提供了依据。

abstractsObjective:To determine the types of genetic variants in six Chinese pedigrees affected with Marfan syndrome (MFS) and analyze their clinical characteristics and molecular pathogenesis.Methods:Six 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). Results:Cardiovascular 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-dimensional structure indicated that the six variant sites in the amino acid sequence are all close to hydrogen bonds and may alter the secondary and tertiary structures to varying degrees, thereby confirmed the relationship between the variants and MFS. Conclusion:Four novel variants of the FBN1 gene have been discovered in this study, which has enriched the mutational and phenotypic spectrum of MFS and provided a basis for disease diagnosis and genetic counseling.