Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections

Abstract

Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-β receptor-1 (TGFBR1) and transforming growth factor-β receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

“…First, variable penetrance, which often characterizes NS‐TAD forms, is a potential confounder. This results in intrafamilial variability, which is evident not only with reference to the aortopathy itself (severity, age of onset), but also with regard to other phenotypic manifestations 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81. The presence of associated features is certainly suggestive of having inherited the aortic condition along with the predisposition to the aortopathy, but the absence of these associated features does not eliminate the risk of having an underlying aortopathy.…”

Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

“…A recent study observed an association with truncating and splicing mutations in Chinese patients with cardiovascular defects (dilatation, aneurysm, and dissection). 11 Others have not reported an association with truncating mutations or cysteine mutations and cardiovascular manifestations. 6,[12][13][14] One reason that others may not have observed an association is because of the way the data were analyzed, for example, lumping dilatation and dissection and/or mitral valve prolapse together, including in the analysis patients who are too young to manifest cardiovascular events, and/or including patients who were older and more likely to manifest cardiovascular events.…”

Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants

“…In 2013, Wang and coworkers performed, for the first time, mutational analysis on FBN1, TGFBR1 and TGFBR2 genes (the three most common genes causing familial TAA) in 29 TAA Chinese patients (7 affected families and 22 sporadic patients), and found 21 mutations. In particular, they provided evidence that lack of exon 47 skipping of FBN-1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAA [16].…”

“…Familial TAAD can be subdivided into syndromic presentations that show prominent features of a systemic connective tissue disorder (such as Marfan, Loeys-Dietz and Ehlers-Danlos syndrome) and nonsyndromic presentations (such as bicommissural aortic valve with TAA, and isolated familial TAA). Seven susceptibility loci have been associated with TAA syndromic and non-syndromic forms (see Table 3) [12][13][14][15][16]. Related-genes have revealed that perturbed extracellular matrix signaling cascade interactions, deficient intracellular components of the smooth muscle contractile apparatus and deregulation of transforming growth factor-β cytokine (TGF-β) pathway are the key TAA mechanisms (see Table 3) [2,[17][18][19][20].…”