[ ABSTRACT] AIM:To investigate the genetic cause of 2 Chinese families with Marfan syndrome .METHODS:The clinical and laboratory investigations were performed in the 2 unrelated Chinese families .Family 1 had 1 patient with cardiac problem.Family 2 had 2 patients:one died, and the other with respiratory and cardiac problems .Next generation sequencing and Sanger sequencing in the Marfan syndrome causal gene FBN1 were performed in the patient , his unaffected sister and the parents of family 1.Sanger sequencing covering all the exons and intron-exon boundaries were performed in the patient and the parents in family 2.Bioinformatic analysis was engaged in the variations unravelled .Fifty healthy indi-viduals were also investigated in the same manner .RESULTS:Both patients were diagnosed with Marfan syndrome .A no-vel mutation c.4685G>A (p.Cys1562Tyr) was detected in the patient of family 1 but was absent in his parents and the unaffected sister .This is a previously unreported novel mutation .In the mutation a conserved Cys was substituted by a Tyr in amino acid 1562 affecting a TGF-βbinding domain and the secondary structure in the encoded protein .We also detected the mutation c.3706T>C (p.Cys1236Arg) in the patient of family 2.It was absent in the unaffected parents , and there-fore was a de novo mutation too.This mutation has been previously reported and known to be associated with neonatal Marfan syndrome .Both mutations were absent in the 50 healthy controls .We also compared the genotype and phenotypes of the 2 families.CONCLUSION:We report 2 de novo mutations in 2 Chinese families with Marfan syndrome .One of the 2 mutations is novel.The phenotype of the mutation c.4685G>A(p.Cys1562Tyr) in family 1 is associated with classical Marfan syndrome, while that of c.3706T>C (p.Cys1236Arg) in family 2 is with neonatal type of Marfan syndrome .De novo mutations may be a cause for a proportion of mutations underlying the disease .The novel mutation also expends the mutational spectrum of the FBN1 gene.%目的：本研究对2个不同马凡综合征（ Marfan syndrome ）的小家系进行致病基因FBN1的编码区和剪切位点突变检测，以寻找致病的突变，并初步探索马凡综合征基因型-表型的关联。方法：通过临床检查、实验室检查及心脏超声检查确诊2个无血缘关系的家庭中原疑似为马凡综合征的3例患者。运用新一代测序对家系1的疑似患者行FBN1基因的全外显子组测序，并对检出的致病性遗传变异进行Sanger验证及在所有家系成员中验证；对于家系2的存活成员，本研究直接进行PCR扩增FBN1基因的所有编码区及剪切位点，对产物进行直接San-ger测序。另外在50个正常对照中对新发现的突变位点进行基于PCR产物的测序分析，以排除多态性；并对实验结果行生物信息学分析。结果：所有存活的疑似患者均确诊为马凡综合征。在家系1中，我们检测到了一个FBN1基因数据库中尚未报道的新突变c．4685G＞A（p．Cys1562Tyr），并且患者父母和同胞姐姐均未检测到此变异，故此突变为一个新生突变。该错义突变使第1562位上极性中性的含硫的半胱氨酸被极性中性的含羟苯基的酪氨酸所替代，影响了fibrillin-1蛋白一个TGF-β结合结构域，导致蛋白质的二级结构发生改变。家系2含父母及一对同卵双胎患者，其中一患者已去世。我们在存活患者检测到1个 FBN1基因的已报道致病突变 c．3706T ＞C （ p． Cys1236Arg），该突变在患者父母中不存在，故也为新生突变。结论：本文报道了一例FBN1基因的新突变及另一例由FBN1基因已知突变引起的马凡综合征，二者皆为新生突变，并在家系中进行了基因型-表型的比较，表明家系1的新突变可能与经典马凡综合征的表型相关，而家系2的已知突变确和新生儿重症马凡综合征表型相关。
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