Mutations in a XXXX Ligand, @entity1934 , Cause  @entity449 and  Dissections.

@entity1 @entity449 @entity339 @entity7379 @entity1614 @entity2334 @entity397 @entity439 @entity1934 @entity2533 @entity19844 @entity36618 @entity85 @entity2419 @entity6474 @entity65
BACKGROUND: @entity439 affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or @entity397 . Investigations of the pathogenic mechanisms involved in syndromic types of @entity2334 , such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-b signaling. OBJECTIVES: This study sought to discover a novel gene causing @entity449 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 @entity2334 . Extensive cardiological 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 @entity1 from 11 families with syndromic presentations of @entity449 caused by @entity1934 mutations. We demonstrate that @entity1934 mutations are associated with significant @entity65 , including @entity2334 , and @entity339 . Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and @entity1614 , including @entity2419 , @entity36618 , skeletal overgrowth, cervical spine instability and @entity85 . In line with previous observations in aortic wall tissues of @entity1 with mutations in effectors of @entity2533 signaling ( @entity19844 , @entity7379 , and @entity6474 ), we confirm a paradoxical up-regulation of both canonical and noncanonical @entity2533 signaling in association with up-regulation of the expression of @entity2533 ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with @entity1934 mutations and highlight  the  importance of early recognition of the disease because of high cardiovascular risk.
