Aortic Aneurysm, Familial Thoracic 8

A number sign (#) is used with this entry because of evidence that thoracic aortic aneurysm-8 (AAT8) is caused by heterozygous mutation in the PRKG1 gene (176894) on chromosome 10q11.

Clinical Features

Tran-Fadulu et al. (2006) described 3 families with autosomal dominant inheritance of thoracic aortic aneurysms leading to either type A or type B dissections and a young age of onset of aortic dissections in both men and women. One family (TAA216) was a large 6-generation pedigree in which the second-generation matriach died suddenly at 35 years of age from rupture of the ascending aorta, with cystic medial necrosis noted on pathology. One of her daughters died suddenly at 18 years of age due to type A aortic dissection with rupture; a second daughter died of type A dissection at 45 years of age, with medial degeneration noted on pathology. A third daughter had type A aortic dissection at 37 years of age, and underwent repair, but died a year later of unknown causes. The second daughter had 12 children, half of whom had aortic disease: in addition to thoracic aortic aneurysms, 2 also had abdominal aortic aneurysms, 2 had aneurysms of the interatrial septum, 1 had mild tortuosity of the ascending aorta, and 1 had a subcutaneous arteriovenous aneurysm of the hand.

Mapping

Tran-Fadulu et al. (2006) studied 3 families segregating autosomal dominant thoracic aortic aneurysms (AAT) with a young age of onset of dissection. Genetic analysis of 1 of the families (TAA216) excluded linkage to known AAT loci (see 607086) and the FBN1 gene (134797). The authors hypothesized that the other 2 families would also be distinct from known loci based on their phenotypic similarity to the larger pedigree.

In 4 families with thoracic aortic aneurysm and dissection, 1 of which was the large 6-generation family previously studied by Tran-Fadulu et al. (2006), Guo et al. (2013) performed 2-point linkage analysis of disease with a variant in the PRKG1 gene (see MOLECULAR GENETICS) and obtained a combined lod score of 7.88.

Molecular Genetics

By exome sequencing in a large 6-generation family segregating autosomal dominant thoracic aortic aneurysm and dissection, originally described by Tran-Fadulu et al. (2006) (family TAA216), Guo et al. (2013) excluded mutations in known genes associated with familial thoracic aortic disease and identified a heterozygous missense mutation in the PRKG1 gene (R177Q; 176894.0001). Analysis of exome data from 55 unrelated AAT probands identified heterozygosity for the same R177Q variant in the probands from 2 more families (TAA508 and TAA690), and Sanger sequencing of PRKG1 in another 307 probands identified R177Q in a fourth family (TAA292). The mutation segregated with disease in each family, and thoracic aortic disease was fully penetrant in family members over 18 years of age. Acute aortic dissection occurred as young as 17 years of age and was equally penetrant in men and women. Review of patient records for additional vascular disease revealed the presence of enlargement of the descending thoracic aorta, abdominal aorta, and other arteries in some patients. In family TAA508, 1 affected individual also had a giant coronary artery aneurysm and another had a spontaneous coronary artery dissection and ectatic coronary arteries. Tortuosity of the thoracic aorta was noted in 2 patients from family TAA216 and in 1 patient from family TAA292. Guo et al. (2013) stated that none of the mutation-positive patients who were examined by a clinical geneticist had features of Marfan syndrome (see 154700) or any other genetic syndrome associated with thoracic aortic disease (see, e.g., 609192).

Pathogenesis

Guo et al. (2013) examined aortic tissue from affected individuals from families TAA216 and TAA292 and observed the typical pathology associated with thoracic arotic disease, including increased proteoglycan accumulation, decreased smooth muscle cells, and elastic fiber loss and fragmentation. There was a substantial increase in small arteries in the medial layer from the vasa vasorum in PRKG1-mutation-positive individuals compared to controls. Guo et al. (2013) noted that similar invasion of the vasa vasorum into the medial layer had previously been seen in the aortas of individuals with MYH11 (160745) and MYLK (600922) mutations (Pannu et al., 2007; Wang et al., 2010).