Abstract 4523: Sequencing of the Known Genes for Thoracic Aortic Disease in the GENTAC (Genetically-triggered Thoracic Aortic Aneurysms and Related Conditions) Cohort
Objective: Thoracic aortic aneurysms leading to aortic dissections (TAAD) have a significant contribution from single gene mutations with 6 genes identified to date. The NHLBI-supported GenTAC (Genetically-triggered Thoracic Aortic Aneurysms and Related Conditions) registry collects clinical data and samples on patients at risk for genetically-triggered thoracic aortic disease due to known syndromes (Marfan syndrome (MFS; gene FBN1), Loeys-Dietz syndrome (LDS; TGFBR1 and TGFBR2), vascular Ehlers Danlos syndrome (vEDS, COL3A1), Turner syndrome (TS)) and patients with clinical evidence of genetically triggered aortic disease such as familial TAAD (FTAAD), bicuspid aortic valve and TAAD (BAV/TAAD), and onset of TAAD <50 years of age. We sought to characterize the gene mutations in the GenTAC cohort.
Methods: Of the initial 710 GenTAC patients enrolled through Dec 2008, 103 patients entered with known mutations (56 FBN1 in MFS patients, 4 TGFBR1 and 4 TGFBR2 in LDS, and 4 COL3A1 in vEDS) and 35 patients had TS. 47 patients did not have TAAD. We sequenced the remaining 560 GenTAC patients (35% MFS, 33% BAV/TAAD, 16% FTAAD, 16% other) for variants in the 6 known genes for TAAD; FBN1 data are pending. Preliminary analysis is presented on variants previously shown to cause disease (19) and possible mutations based on predicted protein truncation or protein structural changes (8).
Results: Amongst potential mutations that are in the process of confirmation, there were 1 frameshift and 6 missense variants identified in TGFBR1, and 3 missense changes in TGFBR2. Only one of these patients was diagnosed with LDS at the time of GenTAC enrollment and the others are being reassessed for features of LDS. COL3A1 mutations were identified in 3 vEDS (one patient had 2 mutations) and 4 patients with aortic disease that did not carry an initial diagnosis of vEDS (although diagnoses are being reassessed). Potential mutations also included ACTA2 missense variants in 3 patients with FTAAD and MYH11 variants in 4 patients with FTAAD.
Conclusions: The rarity of mutations in 5 TAAD genes in the GenTAC patients who do not have MFS indicates further research needs to be done to identify genes predisposing to TAAD. Resequencing, Univ of Washington, Dept. Genome Sciences, N01-HV-48194 NHLBI.