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Open Access Highly Accessed Research article

Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome

Guglielmina Pepe12*, Stefano Nistri13, Betti Giusti12, Elena Sticchi12, Monica Attanasio12, Cristina Porciani12, Rosanna Abbate12, Robert O Bonow4, Magdi Yacoub5 and Gian Franco Gensini126

Author Affiliations

1 Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities; DENOTHE Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy

2 Department of Heart and Vessels, Regional Marfan Syndrome and Related Disorders Center, Careggi Hospital, Florence, Italy

3 Cardiology Service, CMSR Veneto Medica, AltavillaVicentina, Italy

4 Department of Medicine, Northwestern University, Chicago, IL, USA

5 Heart Science Centre, Imperial College, London, UK

6 S. Maria agli Ulivi Center, Fondazione Don Carlo Gnocchi, Onlus, IRCCS, Florence, Italy

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BMC Medical Genetics 2014, 15:23  doi:10.1186/1471-2350-15-23

Published: 24 February 2014



Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined.


Ten consecutive BAV patients [8 men, age range 24–42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients.


We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype.


The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing.

Bicuspid aortic valve; Aortic disease; Aneurysm; Marfan syndrome; Fibrillin-1