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Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55 Page 9 of 15

THSD4: Exome and next-generation sequencing of 35 families with TAAD and 1,114 unrelated TAAD
patients, respectively, identified two heterozygous nonsense mutations in THSD4, which encodes the
[53]
microfibril-associated protein ADAMTSL6 . This protein promotes fibrillin-1 matrix assembly, and these
loss-of-function variants result in impaired assembly that correlates with progressive dilation of the thoracic
aorta. Histologic staining of aortic samples from affected individuals demonstrates medial degeneration and
diffuse ECM disruption.

FBN-1: Perhaps the most well-known mutation in TAAD is FBN-1, which encodes fibrillin-1 and is the
etiology of MFS. However, multiple studies have found that patients who presented with TAAD but did not
meet the Ghent criteria for MFS also exhibit genetic variations at FBN-1 [54-57] . These studies suggest that
mutation of fibrillin-1 plays a role in the pathophysiology of ns-TAAD that is distinct from but not
dissimilar to that of s-TAAD.

Gene mutations in TGF- signaling
[58]
TGFB2: Most commonly associated with LDS , loss-of-function mutations in TGFB2 have also been found
to cause ns-TAAD. Using genome-wide linkage analysis followed by exome sequencing in two large families
with non-syndromic thoracic aortic disease, Boileau et al. identified four mutations in TGFB2 causing
haploinsufficiency in affected individuals . The gene encodes transforming growth factor beta-2 (TGF-2),
[59]
an important cell signaling molecule, and has paradoxically increased expression in diseased thoracic aortic
tissue. The exact mechanism of this phenomenon has yet to be fully elucidated.

TGFBR1 and TGFBR2: Also underpinning LDS, TGFBR1 and TGFBR2 variants have been found in ns-
TAAD. The genes encode two TGF-2 receptors involved in TGF-/Smad cell signaling. Pannu et al.
identified TGFBR2 mutations affecting Arg460 in the cytoplasmic serine-threonine kinase domain of the
[60]
receptor in four of 80 families with ns-TAAD using exon sequencing . Affected individuals presented with
predominantly ascending aortic disease (aneurysm or Type A dissection); descending aortic and medium-
vessel aortopathy was also present. Data from the Montalcino Aortic Consortium, an international registry
of patients with heritable thoracic aortic disease, revealed ns-TAAD patients with a TGFBR1 mutation have
a greater aortic risk, particularly if they are female, but a TGFBR2 mutation was associated with smaller
[61]
aortic root diameter prior to or at the time of type A aortic dissection .

SMAD3: SMAD proteins play an integral role in downstream TGF- signaling in gene expression. Loss-of-
function SMAD3 mutations are strongly associated with LDS type 3 (aneurysms-osteoarthritis syndrome)
but were found by Regalado et al. to also be responsible for 2% of ns-TAAD with a mean age at dissection of
42 years old [62,63] . Importantly, they also found that 19% of individuals carrying a variant in SMAD3
experienced extra-thoracic disease - abdominal aortic aneurysm, iliac artery aneurysm, or intracranial
[62]
aneurysm - which argues for screening for other aneurysmal sites in those carrying a SMAD3 variant .

SMAD4: Smad4 is a central mediator protein in the canonical TBF- signaling pathway in implicated in ns-
TAAD. Zhang et al. first described the role of Smad4 in aortic aneurysm pathogenesis using a conditional
[64]
gene knockout mouse model . Deletion of Smad4 in VSMCs led to the development of thoracic aortic
aneurysm and subsequent death from aneurysm rupture in all affected mice, positing that Smad4 is integral
to aortic wall homeostasis. In 2019, Duan et al. identified a loss-of-function SMAD4 variant for the first time
in humans with ns-TAAD. SMAD4 is canonically associated with TAAD in individuals with a concurrent
diagnosis of juvenile polyposis syndrome (JPS), hereditary hemorrhagic telangiectasia (HHT), or combined
JPS-HHT [65-67] . This Smad4 heterozygous missense mutation (p.Arg97Leu) was newly identified in
individuals with thoracic aortopathy but no diagnosis of JPS or HHT . This mutation resulted in increased
[67]