Thoracic Aortic Aneurysm and Dissection (TAAD) via the ACTA2 Gene

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease affecting the aorta and is the 15th leading cause of death in the United States (Hoyert et al. 2001. PubMed ID: 11591077). The major manifestations of TAAD include dilatation of the aorta, aortic aneurysms and aortic dissection. Aortic dissections most commonly originate in the ascending aorta above the aortic valve (Stanford type A), but also can occur in the descending aorta (Standford type B). Aneurysms in the cerebral and peripheral artery and abdominal aorta have also been observed (Milewicz and Regalado. 2012. PubMed ID: 20301299). An intense sharp pain in the chest is the most common symptom of aortic dissection. Familial TAAD is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta using imaging studies (MRI, echocardiography, CT), the absence of syndromic conditions that have clinical features that overlap with familial TAAD, such as Marfan syndrome, Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome, and a positive family history. Up to 20% of individuals with TAAD have a first-degree relative with TAAD (Biddinger et al. 1997. PubMed ID: 9081132; Albornoz et al. 2006. PubMed ID: 16996941). Aortic imaging is recommended in first degree relatives of individuals with TAAD (Milewicz and Regalado. 2012. PubMed ID: 20301299). Age of onset of dilatation is variable within families.

TAAD is a genetically heterogeneous disorder with incomplete penetrance and variable expressivity. Pathogenic variants in at least 17 genes, including ACTA2, have been found to be associated with autosomal dominant TAAD or related disorders (Milewicz and Regalado. 2012. PubMed ID: 20301299; Milewicz and Regalado. 2015. PubMed ID: 25218541). The vast majority of documented causative variants in ACTA2 are missense, although nonsense, splicing and a small framseshift deletion variants have also been reported (Guo et al. 2007. PubMed ID: 17994018; Guo et al. 2009. PubMed ID: 19409525; Disabella et al. 2011. PubMed ID: 21212136; Renard et al. 2013. PubMed ID: 21937134; Regalado et al. 2015. PubMed ID: 25759435).

The ACTA2 gene encodes the smooth muscle alpha actin which is involved in contraction of the aorta. Some patients with ACTA2 pathogenic variants have livedo reticularis, a purplish skin rash caused by constriction or occlusion of dermal capillaries. Pathogenic variants in ACTA2 are also associated with Moyamoya disease and multisystemic smooth muscle dysfunction syndrome.

This test will detect causative variants in 12-16% of patients with familial TAAD (Guo et al. 2007. PubMed ID: 17994018; Disabella et al. 2011. PubMed ID: 21212136; Renard et al. 2013. PubMed ID: 21937134).

This test provides full coverage of all coding exons of the ACTA2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.