Chapter 2 . 3 Mutations in a TGFß ligand , TGFB 3 , cause syndromic aortic aneurysms and dissections Mutations in TGFB 3 cause syndromic aortic aneurysms and dissections

Background Aneurysms affecting the aorta are a common condition associated with high mortality due to aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed TGFβ signaling. Objective To discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. Methods We combined genome wide linkage analysis, exome sequencing and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiologic examination, including physical examination, electrocardiography and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. Results Here we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg and Marfan syndrome, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and club foot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGFβ signaling (TGFBR1/2, SMAD3 and TGFB2), we confirm a paradoxical upregulation of both canonical and non-canonical TGFβ signaling in association with upregulation of expression of TGFβ ligands. Conclusions Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease due to high cardiovascular risk. 2 Erasmus Medical Center Rotterdam