Thoracic Aortic Aneurysm and Dissection (TAAD) via the PRKG1 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). 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). 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 the 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; Albornoz et al. 2006). Aortic imaging is recommended in first degree relatives of individuals with TAAD (Milewicz and Regalado 2012). Age of onset of dilatation is variable within families.

TAAD is a genetically heterogeneous disorder with reduced penetrance and variable expressivity. Pathogenic variants in at least 10 genes, including PRKG1, have been found to be associated with autosomal dominant TAAD (Guo et al. 2013; Gago-Diaz et al. 2016). One missense variant, c.530G>A (p.Arg177Gln), has been shown to segregate with TAAD in five families (Guo et al. 2013; Gago-Diaz et al. 2016). Individuals with the c.530G>A (p.Arg177Gln) variant had early-onset TAAD (Guo et al. 2013; Gago-Diaz et al. 2016). PRKG1 encodes a cGMP-dependent protein kinase which controls smooth muscle relaxation (Pfeifer et al. 1998).

Clinical sensitivity for PRKG1 is predicted to be low; one study found the c.530G>A (p.Arg177Gln) variant in three out of 362 families (Guo et al. 2013).

This test provides full coverage of all coding exons of the PRKG1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.