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Page 6 of 15 Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55

Genetics
Multiple genes have been identified in the development of ns-TAAD. Unlike MFS and other connective
tissue disorders, highly penetrant single-gene variants (i.e., Mendelian inheritance) are unlikely to be
associated with certain clinical characteristics or hereditary patterns. Familial ns-TAAD is more likely to be
associated with previously identified genes, but sporadic ns-TAAD has recently been found to result from
pathogenic copy number variants and genetic polymorphisms. Currently, 11 genes have been validated to
cause heritable thoracic aortic disease, and 17 genes have a putative hereditary association awaiting
[15]
confirmational evidence (as of 2021) . While some have only been identified in ns-TAAD, many others are
connected with both ns-TAAD and syndromic thoracic aneurysm and dissection (s-TAAD) [15,36] , which
again highlights the difficulties in understanding the pathogenesis of ns-TAAD. These genetic mutations
result in dysregulation of TGF- signaling, inappropriate remodeling of extracellular matrix (ECM), and
[37]
disruption of VSMC function .

As many ns-TAAD are present in patients without pathognomonic syndromic features, the identification of
pathogenic genes significantly impacts the diagnosis and management of ns-TAAD. The ClinGen
Aortopathy Expert Panel reviewed 53 genes that have been found to have some association in hereditary
TAAD and categorized them into the strength of association in thoracic aortopathy, with category A1
indicating “definitive” association and A2 indicating “strong” association. Variants in five genes (ACTA2,
MYH11, MYLK, LOX, PRKG1) were categorized as A2 in association with ns-TAAD [38,39] . Several other
genes, including FBN1, SMAD3, TGFB2, TGFBR1, and TGFBR2, have observed genome variants that are
associated with both ns- and s-TAAD. A list of key genes discussed herein is listed in Table 1.

Gene mutations in vascular smooth muscle cells
The major responsibility of VSMCs is contraction in response to pulsatile blood flow to mitigate stretch and
return the vessel to normal diameter. Contraction relies on -actin and -myosin cyclic interaction to
maintain proper vascular tone. The following genomic pathways are important for the proper development
of the -actin and -myosin contractile units. Mutations in these genes, some within the same pedigree,
highlight the significant degree of phenotypic variance.

ACTA2: Mutations in the ACTA2 gene resulting in modification of VSMC -actin protein and improper
filament assembly are responsible for 15% of familial ns-TAAD. Guo et al. conducted a study of a large
family of over four generations demonstrating an autosomal dominant inheritance pattern of ns-TAAD
with decreased penetrance but who were found to not have a known genetic mutation. Genome-wide
linkage analysis identified an inherited missense mutation in ACTA2 that results in a dominant-negative
mechanism that decreases actin filament assembly. Further sequencing of an additional 97 unrelated but
affected families identified 14 families with the ACTA2 mutation. Interestingly, ACTA2-mutation carriers
also presented with other vascular abnormalities, including livedo reticularis, iris oculae, and patent ductus
arteriosus (PDA). Penetrance of TAAD was variable and did not increase with age .
[40]
MYH11: Multiple studies have found missense mutations in MYH11, a gene encoding VSMC-specific
[37]
isoforms of myosin heavy chain proteins, to be associated with ns-TAAD in about 1% of cases . Zhu et al.
first identified MYH11 mutations in one unrelated French and one American family presenting with
TAAD. The mutations have a dominant-negative mechanism resulting in an abnormal C-terminal coiled-
coil region of the myosin heavy chain specific to smooth muscle cells. Zhu demonstrated incomplete
penetrance of TAAD in addition to members of both families carrying a diagnosis of PDA. Notably,
asymptomatic carriers of the mutation in both families had normal aortic diameters but were found to have
decreased aortic compliance and increased pulse wave velocity, suggesting early manifestations of