Bence Ágg1,2, Roland Stengl1,2, András Bors3, Hajnalka Andrikovics3, Kálmán Benke1,2, Noémi Daradics1,2, Miklós Pólos1,2, Béla Merkely1, Zoltán Szabolcs1,2
1Heart and Vascular Center, Semmelweis University, Budapest
2Hungarian Marfan Foundation, Budapest
3Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest, Hungary
Introduction: Marfan syndrome (MFS), a systemic connective tissue disorder is caused by one of the multiple thousand known mutations of the FBN1 gene, resulting in decreased availability of the fibrillin-1 protein (haploinsufficiency, HI) or altered structure of the protein product (dominant negative mutation, DN). Aortic dissection, which is a life-threatening complication of the syndrome, could be prevented by a timely prophylactic aortic root replacement (ARR) surgery. However, following the currently available guidelines does not guarantee optimal timing of prophylactic surgical intervention.
Aims: To develop a better, genotype-based cardiovascular risk stratification, we aimed to investigate genotype-phenotype correlations in MFS.
Method: In case of 54 MFS patients clinical manifestations were assessed according to the Ghent nosology. Mutations of the FBN1 gene were analyzed by next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) technology.
Results: 37 pathogenic mutations (69%) consisting of 19 DN and 18 HI cases were identified. In case of HI mutations a tendency of increased risk for major cardiovascular events was observed (HI: 16/18; DN: 12/19; p=0.068). Out of the 19 DN mutations 12 cases involved a cysteine residue, in 10 cases with major cardiovascular manifestations. Cardiovascular symptoms were significantly less frequent in case of patients with non-cystein DN mutation compared to cases with HI or cysteine DN mutation (p=0.001). 18 out of the total 19 ARR surgeries were performed on patients with HI (7) or cysteine DN (11) mutations. All 4 cases of acute aortic dissection developed in patients with cysteine DN mutation.
Conclusion: We showed that DN mutations involving cysteine residues are associated with an increased cardiovascular risk. Therefore by enabling predictions on the severity of the aortic involvement, identification of the type of pathogenic mutations in FBN1, could help to better select the optimal timing of prophylactic ARR surgeries in MFS.
Doctoral School: Pharmaceutical Sciences
Program: Experimental and Clinical Pharmacology
Supervisor: Prof. Zoltán Szabolcs, MD, PhD
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