Genetics of HTAD

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HTAD is caused by pathogenic variants in genes that are essential for maintaining the strength, elasticity, and biological regulation of the aortic wall. These genes fall into several functional groups, including those involved in connective tissue structure, smooth muscle cell contraction, and signaling pathways that regulate growth and repair.

International expert review has identified a core set of eleven genes with strong or definitive evidence for causing heritable thoracic aortic disease. Variants in these genes are considered clinically actionable, meaning they are used to guide medical care and family screening.

Genes with strong or definitive evidence for HTAD

The following eleven genes are currently recognized as having strong or definitive evidence for causing HTAD:

  • FBN1 – associated with Marfan syndrome
  • TGFBR1 and TGFBR2 – associated with Loeys–Dietz syndrome types 1 and 2
  • SMAD3 and TGFB2 – associated with Loeys–Dietz syndrome types 3 and 4
  • COL3A1 – associated with vascular Ehlers–Danlos syndrome
  • ACTA2 – associated with non-syndromic HTAD and smooth muscle dysfunction syndrome (SMDS)
  • MYH11 – associated with non-syndromic HTAD
  • MYLK – associated with non-syndromic HTAD
  • LOX – associated with non-syndromic HTAD
  • PRKG1 – associated with non-syndromic HTAD

Together, these genes account for a substantial proportion of individuals with heritable thoracic aortic disease, although not all families will have an identifiable variant.

Most HTAD-associated conditions are inherited in an autosomal dominant pattern, but penetrance and expression are variable. This means that not everyone who carries a disease-causing variant will develop the same degree of aortic disease, and some individuals may not develop noticeable disease until later in life.

Genetic testing may also identify variants of uncertain significance (VUS). These are genetic changes for which there is not yet enough evidence to determine whether they cause disease. VUS results are not used alone to guide treatment or family testing, but they may be reclassified over time as more data become available through research and international registries.

Understanding the genetic basis of HTAD allows care to be individualized. Genetic information can help determine which parts of the aorta and other arteries should be monitored, how often imaging should be performed, and which family members may benefit from evaluation. Ongoing research continues to refine how specific genes influence risk and outcomes in heritable aortic disease.

Scientific sources and further reading

  • Heritable Thoracic Aortic Disease Overview – GeneReviews®
  • Genetics of Heritable Thoracic Aortic Disease – Cardiogenetics
  • Clinical validity of genes for heritable thoracic aortic disease – Journal of the American College of Cardiology
  • Update on the genetic risk for thoracic aortic aneurysm and dissection – Journal of Cardiovascular Surgery
  • Marfan syndrome, Loeys–Dietz syndrome, and Vascular Ehlers–Danlos syndrome – GeneReviews®