The Ghent Center for Medical Genetics has a longstanding expertise in studying clinical and molecular aspects of heritable connective tissue disorders. A multidisciplinary setting for clinical assessment of patients with heritable connective tissue disorders such as Marfan syndrome and related diseases has been established. This provides access to extended phenotypic information and patient samples (fibroblasts, vascular smooth muscle cells, DNA) from over 500 patients with Marfan syndrome and related connective tissue disorders, and of patients with thoracic aortic aneurysms and/or bicuspid aortic valves. In addition, this center has also created an extended molecular facility for molecular studies on genes encoding different extracellular matrix proteins including collagens, fibrillins 1 and 2, GLUT10, TGF-beta receptor 1 and 2, MYH 11 and fibulins-4 and 5. In this way, close integration of clinical and molecular findings enhances possibilities to study these disorders.

Facilities description: the lab is equipped with a semi-automated mutation detection setting containing pre -and post PCR robots (Tecan, Caliper), two denaturing High Performance Liquid Chromatography systems (DHPLC, Transgenomics), Light Cycler 450 (Roche), Light Scanner (Idaho), ABI 3130 (16 capillary) and ABI3730 (96 capillar)). Also a cell culture facility, a fluorescence microscopy, functional assays (Western blotting, protein expression, purification and characterization, in vitro expression studies) are available in the lab.

Tasks in FAD:

establish TAA clinical and biological database; WP2: study the genetic factors which contribute to aortic aneurysm formation by : 1) identifying mutations and new genes underlying aortic aneurysms/bicuspid aortic valve disease; 2) studying genetic variation underlying aneurysm syndromes (by functional SNP analysis in genes encoding extracellular matrix proteins and components of the TGFbeta signalling pathway); 3) by creation and characterisation of new knock-in mouse models and study aortic tissues from these animals by light microscopy, qPCR and immunohistochemistry. WP4: automated system for direct sequencing of genes in TAA.

Members of the FAD staff:

Main publication/patent linked to FAD tasks

 Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De BackerJF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA,Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006; 355:788-798.
 De Backer J, Loeys B, Devos D, Dietz H, De Sutter J, De Paepe A. A critical analysis of minor cardiovascular criteria in the diagnostic evaluation of patients with Marfan syndrome. Genet Med. 2006; 8:401-408.
 Coucke PJ, Willaert A, Wessels MW, Callewaert B, Zoppi N, De Backer J, Fox JE, Mancini GM, Kambouris M, Gardella R, Facchetti F, Willems PJ, Forsyth R,Dietz HC, Barlati S, Colombi M, Loeys B, De Paepe A. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006; 38: 452-457.
 Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J,Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005; 37: 275-281.
 Callewaert BL, Loeys BL, Casteleyn C, Willaert A, Dewint P, De Backer J, Sedlmeier R, Simoens P, De Paepe AM, Coucke PJ. Absence of arterial phenotype in mice with homozygous slc2A10 missense substitutions. Genesis. 2008;46(8):385-389.
 Malfait F, Symoens S, De Backer J, Hermanns-Lê T, Sakalihasan N, Lapière CM, Coucke P, De Paepe A. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007 Apr;28(4):387-95.