A large family was identified with autosomal dominant inheritance of ascending aortic aneurysms involving the sinuses of Valsalva that is linked to a novel TAAD locus, termed TAAD5
. Serial aortic imaging studies of at least one affected family member indicate a minimal rate of aortic enlargement of less than 0.1 cm per year, which is considerably slower than the 0.21 cm per year reported for patients with FTAAD.4
Only one out of nine affected family members progressed to an acute aortic dissection despite the advanced age of many affected family members. Interestingly, none of the women in this family who carry the disease-linked microsatellite haplotype are affected with TAAD, including an 84 year woman, suggesting reduced penetrance in women. Among 12 males who carried the affected microsatellite haplotype, only nine have aortic root aneurysms, also indicating reduced penetrance in men. The average diameter of the root aneurysms is 4.7 cm at the age of diagnosis and the average age at diagnosis is 55 years.
The major risk factors for aortic dissections include the diameter of TAA, rate of aneurysm enlargement, and hypertension.11;12
Despite a recommendation to repair thoracic aortic aneurysms with diameters over 5.0 cm, there is significant variability in the risk of dissection based on size, with a subset of aneurysms dissecting with no aortic enlargement while other aneurysms do not dissect even at large aortic diameters of over 10 cm.13
Another identified risk for dissection is a rapidly expanding aneurysm, defined as greater than 0.5 cm increase in a year, particularly if the patient is young or is known to have inherited a genetic predisposition for the aneurysm.14
The low risk for aortic dissection associated with the aneurysms in the family reported here was most likely the result of a slow rate of enlargement of the aneurysms and a low risk of dissection at diameters less the 5.0 cm.
Accumulating data suggest that the underlying gene predisposing an individual to thoracic aortic disease predicts the risk of aortic dissection at a given aortic diameter of an ascending thoracic aneurysm. For example, Marfan syndrome is an autosomal dominant condition resulting from mutations in FBN1
, and associated with TAAD, skeletal manifestations and ocular complications.15;16
Loeys-Dietz syndrome (LDS) also predisposes individuals to TAAD and is caused by mutations in either TGFBR1
Although both syndromes cause aortic root aneurysms, TGFBR2
mutation patients are at a high risk of aortic dissections at relatively small aortic diameters, with reported dissections occurring with minimal enlargements (4.2 cm.).14;17
In contrast, patients with FBN1
mutations are at a low risk for dissection at aortic diameters less than 5.0 cm.16
Therefore, knowing the causative gene mutation not only makes it possible to identify family members who are at risk to develop aortic disease but also predict the aortic diameter at which a dissection can occur, thereby optimizing the timing for surgical repair of a thoracic aortic aneurysm. Based on the limited information in family TAA254 reported here, the risk of dissection appears minimal until the aortic size is greater than 6.0 cm.
Interestingly, three individuals in this family had bilateral peripheral artery aneurysms at relatively young ages, one of whom has the affected haplotype (III:4) and another is an obligate carrier (II:6). Mutations in either TGFBR1
cause TAAD, along with aneurysms of other arteries, but not specifically involving the iliac or lower peripheral arteries.14
Mutations in COL3A1
cause peripheral artery aneurysms often in the absence of aortic aneurysms, but bilateral peripheral aneurysms involving a specific artery has not been reported in these patients to our knowledge.18
We have identified a similar phenotype of thoracic aortic aneurysms and iliac aneurysms in other families in our cohort of families with two or more members with TAAD (unpublished data). Once the disease gene is identified, we will be able to assess if this gene also causes iliac aneurysms.
locus spans 49 Mb of chromosome 12 and encodes more than 600 genes or putative transcripts. To identify the gene mutation causing TAAD in this family, we sequenced candidate genes in this locus. Because mutations in ACTA2
, and TGFBR2
result in familial TAAD, we focused on genes involved in the maintenance of SMC contractile function.19
, and ITGB7
were sequenced because they encode members of the integrin receptor family, which are heterodimeric membrane glycoproteins that mediate a wide spectrum of cell-cell and cell-matrix interactions. In the arterial wall, integrins are the principal receptors for the extracellular matrix (ECM) and serve as a transmembrane link between the matrix and the actin cytoskeleton and contractile units, therefore coupling the contractile force to the extracellular matrix.20
mutations are a known cause FTAAD, TWF1
(actin-binding protein, homolog 1), LIMA1
(IM domain and actin binding 1), and AVIL
(advillin) were also sequenced because they encode actin binding proteins that are involved in the regulation of actin polymerization, stabilization, and function. In addition, MYL6
, and MYO1A
were also sequenced because these genes encode proteins involved in myofibril structure and function. However, no disease-causing mutation was identified in the exons and intron-exon boundaries of these genes.
Characterization of this family with aortic root aneurysms with a slow rate of enlargement associated with a low risk for aortic dissection provides an example of further clinical heterogeneity associated with FTAAD. Mapping of a novel locus for the aortic disease in this family supports the conclusion that stable aneurysms can be due to a genetic variant at a single locus. We recommended that family members with the risk haplotype be imaged for aortic disease and the ascending aneurysms surgically repaired if the aortic root was greater than 5.0 cm. At the same time, given the low risk for aortic dissection in this family, we are not certain that this is the optimal management of this family.