A novel splicing mutation in Marfan syndrome.

backgroundMarfan syndrome (MFS) is a connective tissue disease involving multiple organs and systems such as cardiovascular, skeletal, and ocular systems and is also an autosomal dominant inheritance disorder.

methodA 30-year-old woman was rushed into the hospital owing to sudden persistent pain in the abdomen and died suddenly 2 days later. To find the real cause of death, a forensic autopsy was conducted owing to suspected medical malpractice, and the diagnosis of MFS was made in accordance with the 2010 revised Ghent nosology. By sequencing the gene of Marfan, aneurysm, and related disorders, a novel splicing mutation in the fibrillin-1 gene (FBN1) was detected. For the clinical characteristic findings (wrist and thumb sign) of the daughter, we recommend genetic analysis for the family. To better understand the role of the variant in the disease, we also investigated functional validation of this mutation.

resultsAccording to the autopsy findings, the cause of death was acute cardiac tamponade caused by aortic rupture. DNA sequencing revealed a novel splicing mutation, c.5672-2delA, which was also detected in her daughter (II2). The functional validation of this mutation showed the base deletion at the same site in the PCR products using cDNA as a template. It is suggested that this mutation may cause abnormal spliceosome during transcription and may encode abnormal protein.

conclusionA novel pathogenic splicing mutation (c.5672-2delA) was confirmed. Present work enriches the profile mutations in FBN1 associated with MFS and stresses the importance of postmortem genetic analysis in such cases.