Familial thoracic aortic aneurysms and dissections: identification of a novel locus for stable aneurysms with a low risk for progression to aortic dissection

Background: Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease.

Methods and results: A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no Other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene.

Conclusions: Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.