关键词: 马凡综合征, FBN1基因, 新发突变, 全外显子测序, 家系筛查

Abstract: Objective To investigate the genetic etiology and analyze the pathogenicity of the detected mutations in three sporadic Marfan syndrome(MFS)patients without family history. Methods Three probands with typical MFS features but no family history who were admitted to Xijing Hospital between 2024 and 2025 were enrolled as subjects.A retrospective study was conducted to collect clinical data from these three families.Peripheral blood samples were collected from the probands and their available family members,and genomic DNA was extracted.Whole-exome sequencing(WES)was performed to screen for genetic variants.Sanger sequencing was used to validate the identified FBN1 gene variants in the probands and their family members.The pathogenicity of the detected variants was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics(ACMG).The potential impact of the variants on protein structure was analyzed via the online tool Mutation Taster and Swiss-Pdb Viewer software. Results Clinical features are as follows:All three probands exhibited cardiovascular system abnormalities.Probands from families 1 and 2 presented ocular abnormalities,whereas all three probands presented skeletal system manifestations.Genetic testing results are as follows:Three different FBN1 gene variants involving three distinct exons were identified across the three MFS families,namely,c.3787T>G(p.Cys1263Gly),c.5965T>C(p.Cys1989Arg),and c.6610T>G(p.Cys2204Gly).Pathogenicity assessment results are as follows:According to the ACMG guidelines,all three variants were classified as“likely pathogenic”.Database and literature searches confirmed that these variants were unreported and thus novel.Parental screening verified that all three mutations were de novo.Bioinformatics analysis results are as follows:Predictions via SIFT and PolyPhen-2 software indicated that the c.3787T>G(p.Cys1263Gly),c.5965T>C(p.Cys1989Arg),and c.6610T>G(p.Cys2204Gly)variants were harmful.Amino acid sequence alignment revealed high conservation of the mutated residues across different species in the FBN1 protein.Comparative analysis of the three-dimensional protein structure revealed that the c.6610T>G(p.Cys2204Gly)variant altered hydrogen bonds in the vicinity of the amino acid,further supporting the association between FBN1 gene variation and MFS. Conclusion This study identified three novel FBN1 gene variants,expanding the mutational and phenotypic spectrum of MFS.Parental testing confirmed their de novo origin,revealing the etiology of sporadic MFS without family history.These findings provide a basis for genetic counseling,clinical diagnosis,and management.

Key words: Marfan syndrome, FBN1 gene, de novo mutation, whole exome sequencing, family screening