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Eur J Cardiothorac Surg 2007;31:970-975. doi:10.1016/j.ejcts.2007.02.027
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?

^a University of Witten/Herdecke, Germany
^b Heart Centre Osnabrück-Bad Rothenfelde, Germany
^c Heart Centre Duisburg, Germany
^d St.-Johannes-Hospital Dortmund, Germany
^e Heart Centre Lahr/Baden, Germany

Received 27 October 2006; received in revised form 26 February 2007; accepted 27 February 2007.

^_* Corresponding author. Address: University of Witten/Herdecke, Institute for Heart and Circulation Research, Heinstueck 11, D-44225 Dortmund, Germany. Tel.: +49 231 72515212; fax: +49 231 72515213. (Email: waldmueller{at}herz-kreislaufforschung.de).

Objective: Mutations in the genes encoding fibrillin-1 (FBN1) and transforming growth factor beta receptor type II (TGFBR2) are known causes of Marfan syndrome (MFS) and related disorders. However, a sound correlation between the genotype and the cardiovascular phenotype has not yet been established. The objective of the present study was to identify novel mutations in FBN1 and TGFBR2 and to assess whether the type of mutation is linked to a particular clinical subtype of the cardiovascular condition. Methods: The clinical records of 36 patients referred to us for molecular genetic diagnosis were reviewed to assess the course and severity of the vascular deterioration. A semiautomatic protocol was established enabling a rapid and cost-effective screening of the genes FBN1 and TGFBR2 by direct sequencing of all coding exons and flanking intronic regions. Results: Novel mutations in FBN1 and TGFBR2 were detected in 12 and 2 patients, respectively. Four individuals carried a recurrent mutation in FBN1. Throughout the study cohort, the incidence of aortic dissections per se did not depend on the type of mutation. However, we found that mutations affecting the calcium-binding epidermal growth factor-like domain were more frequently associated with a dissection of distal parts of the aorta than mutations that lead to a premature termination codon (: p = 0.013), suggesting that the spatio-temporal pattern of vascular deterioration may vary with the type of mutation. Conclusions: Detecting a mutation in the genes FBN1 and TGFBR2 proves the genetic origin of vascular findings and allows the identification of family members at risk who should undergo preventive checkups. Routine genetic testing of patients with suspected MFS or thoracic aortic aneurysms/dissections could provide further insight into genotype/phenotype correlations related to aortic dissection.

Key Words: Mutation • FBN1 • TGFBR2 • Marfan syndrome • Aortic dissection