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. ... 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.
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 ... 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).