A novel splicing mutation in Marfan syndrome
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ORIGINAL ARTICLE
A novel splicing mutation in Marfan syndrome Shuquan Zhao 1 & Yijie Duan 1 & Fang Huang 1 & Qing Shi 1 & Qian Liu 1 & Yiwu Zhou 1 Received: 30 January 2020 / Accepted: 8 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Background Marfan 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. Method A 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. Results According 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. Conclusion A 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. Keywords Marfan syndrome . FBN1 . Splicing mutation . Autopsy . Sudden death
Introduction
Shuquan Zhao and Yijie Duan contributed equally to this work. * Qian Liu [email protected] * Yiwu Zhou [email protected] Shuquan Zhao [email protected] Yijie Duan [email protected] Fang Huang [email protected] Qing Shi [email protected] 1
Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People’s Republic of China
Marfan 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 [1]. The estimated prevalence rate of MFS was 1/5000 in Europe whereas 1–2/10,000 in China with no sex or ethnicity biases [2–4]. Although the clinical manifestations of MFS patients are variant, cardiovascular system lesions are still the leading cause of morbidity and mortality, especially thoracic aortic aneurysm and dissection (TAAD) [1]. It is reported that acute aortic dissection has an hourly mortality rate of 1 to 2% after symptoms in untreated patient
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