Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3’ fibrillin-1 gene mutations with phenotype

Background Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome （MFS）. This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneu rysms/dissection. Methods Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed. Results We found a novel mutation （c.8547T〉G, p.Tyr2849X） in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3＇ end of fibrillin-1 gene （exons 64 and 65）, we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death. Conclusions These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3＇ end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.