Marfan syndrome (MFS) is an autosomal dominant heterogeneous disorder of connective tissue characterized by the early development of thoracic aneurysms/dissections, together with defects of the ocular and skeletal systems. Loss-of-function mutations in fibrillin-1 (FBN1) encoded by the gene, FBN1 (MFS-1), and in the transforming growth factor beta receptor 2 (TGFBR2) gene, TGFBR2 (MFS-2), are major causes of this disorder. In the present study, a rapid and cost-effective method for genetically diagnosing MFS was described and used to identify disease-causing mutations in two unrelated pedigrees with MFS in mainland China. Using targeted semiconductor sequencing, two pathogenic mutations in four MFS patients of the two pedigrees were identified, including a novel frameshift insertion, p.G2120fsX2160, and a reported nonsense mutation, p.Arg529X (rs137854476), in the FBN1 gene. In addition, a rare, probably benign Chinese-specific polymorphism in the FBN1 gene was also revealed.