1. ¹Institute of Human Genetics, Hannover Medical School, Hannover, Germany
2. ²Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

Correspondence: Professor J Schmidtke, Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str.1, D-30625 Hannover, Germany. Tel: +49 511 532 6537; Fax: +49 511 532 5865; E-mail: schmidtke.joerg@mh-hannover.de

Received 29 September 2005; Revised 16 February 2006; Accepted 28 February 2006; Published online 12 April 2006.

Abstract

Marfan syndrome (MFS; OMIM#154700) is a connective tissue disorder characterized by manifestations in the ocular, skeletal and cardiovascular systems. MFS is caused by mutation in the fibrillin-1 gene (FBN1; OMIM#134797) and more than 550 mutations have been identified so far. FBN1 is 230 kb in size and contains three evolutionarily conserved alternatively spliced exons B, A and C at the 5'end. In a first systematic attempt to associate sequence variations in the FBN1 5' alternatively spliced exons with MFS, we investigated 41 individuals fulfilling the diagnostic criteria of Ghent nosology or with features of MFS including at least one major criterion or involvement of two organ systems but not fulfilling a strict interpretation of the Ghent nosology, and known to be negative for mutations in the FBN1 exons 1–65 as well as the TGFBR2 and TGFBR1 coding regions. We identified five novel and one previously reported variants in the six unrelated probands and provide preliminary evidence for their role in pathogenesis.