INTRODUCTION: Marfan syndrome (MFS) (Online Mendelian Inheritance in Man [OMIM] No. 154700) is an autosomal-dominant connective tissue disorder that affects multiple systems including the cardiovascular, ocular, and musculoskeletal systems. Fibrillin 1 (FBN1) (OMIM No. 134797) mutations are causative in >90% of the cases, and recent studies have shown that transforming growth factor β receptor 2 (TGFBR2) (OMIM No. 190182) mutations could be identified in ∼10% of non-FBN1 probands (Mátyás G, Arnold E, Carrel T, et al. Hum Mutat. 2006;27:760–769).
OBJECTIVE: Our objective was to examine the mutation spectrum of TGFBR2 in non-FBN1 Chinese patients with MFS and related phenotypes.
METHODS: All Chinese probands who were referred for evaluation of MFS and tested negative for FBN1 mutations were included. Mutational screening was performed by denaturing high-pressure liquid chromatography (Kosaki K, Udaka T, Okuyama T. Mol Genet Metab. 2005;86:117–123). Amplicons with an abnormal elution pattern were selected for direct sequencing.
RESULTS: Seven novel mutations were identified in 7 of 41 probands. All of them had prominent cardioskeletal phenotypes without ocular or dural involvement, which confirmed previous findings (Disabella E, Grasso M, Marziliano N, et al: Eur J Hum Genet. 2006;14;34–38). Six mutations were missense (R190H, D247V, T325P, G357R, I510N, and T530I), and 1 was frameshift (P501fsX17). Except for R190H, all were found in the functionally important kinase domain. Bioinformatic analyses showed that (1) all mutations occurred in conserved positions by cross-species comparison between 6 orthologs, and (2) R190H, T325P, T530I, and G357R were also found in conserved positions among 3 paralogs (TGFBR1 and activin receptors AVR2A and AVR2B) in the TGFBR superfamily. None of the 7 were found in 50 unaffected individuals (100 normal alleles). With the TGFBR2 mutations, 4 additional probands would fulfill the diagnostic criteria of MFS.
CONCLUSIONS:TGFBR2 mutation was identified in 17% of our non-FBN1 probands. It should be considered in the evaluation for MFS after FBN1 screening, especially if there are compatible clinical features.
Submitted by Hon Yin Brian Chung
- Copyright © 2008 by the American Academy of Pediatrics