CTGT, Familial Anuerysm Syndrome

Collect at NMCP only Mon-Thursday by 1200. 1022 Seq.; 1465 Del / Dup; 1466 Seq. & Del / Dup

1466

Aortic aneurysm, familial thoracic 3 / 4 / 5 / 6 (AAT3 / AAT4 / AAT5 / AAT6) genes: TGFBR2, MYH11, TGFBR1 & ACTA2

4 ml EDTA whole blood (purple top)

4 ml EDTA whole blood (purple top)

4°C

Aortic aneurysm, familial thoracic (AAT) 3 (AAT3; MIM 610380), AAT4 (MIM 132900), AAT5 (MIM 608976), AAT6 (MIM 611788), AAT7 (MIM 613780), SMAD3 related AAT and TGFB2 related AAT are dominantly inherited disorders. AAT5 and AAT3 have been linked to mutations in the transforming growth factor ß receptor type I and II genes (TGFBR1 and TGFBR2). Patients may have aneurysms of the aorta and other arteries. TGFBR2 mutations are currently estimated to be responsible for 5% of familial thoracic aortic aneurysms and dissections (TAAD). AAT4, thoracic aortic aneurysm and/or dissection with patent ductus arteriosus is caused by mutations in the myosin heavy chain 11 gene (MYH11). It is important to note that not all individuals with myosin heavy chain mutations appear to have dilated aortas. These individuals, though asymptomatic, display a low aortic compliance and distensibility due to a decrease in the elasticity of the aortic wall. AAT6 is caused by mutations in the ACTA2 gene, which codes for smooth muscle alpha actin. ACTA2 mutations have been identified in several families to date. Mutations in ACTA2 are estimated to be responsible for 14% of familial thoracic aortic aneurysms. Associated findings in AAT6 caused by ACTA2 mutations may include livedo reticularis, a bicuspid aortic valve, iris flocculi and patent ductus arteriosus. AAT7 is caused by mutations in the MYLK gene. The product of this gene, myosin light chain kinase, phosphorylates the 20 kDa regulatory light chain of smooth and nonmuscle myosin II. Phosphorylation of this molecule is critical for the initiation of smooth muscle contraction. SMAD3 and TGFB2 mutations have also been identified in patients with AAT (SMAD3 related AAT and TGFB2 related AAT). The phenotypes of patients with SMAD3 and TGFB2 mutations are similar. There is also considerable phenotypic overlap with Loeys-Dietz syndrome, type 3 / aneurysms-osteoarthritis syndrome (LDS3 / AOS; MIM 613795) and Loeys-Dietz syndrome, type 4 (LDS4; MIM 614816). SMAD3 mutations are estimated to cause about 2% of AAT cases with or without intracranial or other arterial aneurysms. In two studies, TGFB2 mutations were detected in 1.5% and 25% of sampled familial cases, which had previously tested negative for mutations in other AAT genes.