Familial aneurysm is a heterogenous group of disorders that includes isolated dominantly inherited aortic aneurysm as well as connective tissue disorders in which aneurysmal disease is a component. The phenotype, age of onset and inheritance is determined by the particular causative gene and mutation type.
Step 1. Familial Aneurysm (indistinct phenotype) - VASCULAR PANEL (COL3A1, TGFBR1, TGFBR2, ACTA2, SMAD3)
The Collagen Diagnostic Lab offers testing of FIVE genes for four inherited aneurysmal disorders as a single VASCULAR PANEL as well as testing for individual genes. The decision about which test to choose for your patient is determined by clinical presentation, medical history and family history. If your patient has features that overlap the described disorders, the VASCULAR PANEL yields faster results at a reduced cost per test.
Step 2. Individual Gene Testing
Ehlers-Danlos Syndrome (EDS) type IV - COL3A1 gDNA sequencing
Vascular aneurysm, dissection and/or rupture are common complications of EDS type IV. Over half of the first reported vascular complications involve the aorta. Iliac, renal, mesenteric, splenic, hepatic, coronary and carotid artery complications are described. On average, the first complication is in the third decade with rare events reported in childhood. Recent studies confirm that families with COL3A1 null mutations, a small proportion of all reported mutations, similar vascular events occur with a delayed age of onset.
Loeys-Dietz Syndrome - TGFBR1 and TGFBR2 gDNA sequencing
Mutations in the TGFB receptor genes give rise to clinical phenotypes that overlap with those seen in the Marfan syndrome, including aortic aneurysm, but can include hypertelorism (wide spaced eyes), generalized arterial tortuosity, craniosynostosis, cleft palate, bifid uvula, congenital heart disease, and mental retardation. In some families only aortic root enlargement with risk of early dissection has been recognized while in others the phenotype is more complex. Involvement of vascular vessels other than the aorta are reported as well.
Thoracic Aortic Aneurysm Disorder (TAAD) - ACTA2 gDNA sequencing
Roughly 14% of familial aortic aneurysm results from a dominant missense mutation in ACTA2 on chromosome 17, the gene that encodes a cellular protein, actin, in vascular smooth muscle cells (SMC). Affected family members variably demonstrate thoracic aortic aneurysm and livedo reticularis, a skin finding of a lattice pattern resulting from constriction and occlusion of dermal capillaries. This dermatologic sign is not exclusively seen in TAAD and is not present in all TAAD families. The families show reduced penetrance (40%) making it difficult to reassure relatives of those identified with apparent sporadic disease.
"Aneurysm-Osteoarthritis" (OAS) SMAD3 gDNA sequencing
The most frequent vascular findings in the reported families with a dominant SMAD3 gene mutation were aneurysms of the aorta at the level of the sinuses of Valsalva but also the abdominal aorta and other arteries, and arterial tortuosity. Early-onset osteoarthritis of varying degrees in all affected individuals in the reported family lead to the name "aneurysms-osteoarthritis syndrome (AOS)", but osteoarthritis may not be as frequently present as initially thought. Other common findings involved the skin, skeleton and the craniofacial anatomy. The SMAD3-associated phenotype overlaps significantly with findings in Loeys-Dietz syndrome and, to some extent, with Ehlers-Danlos syndrome (EDS) type IV.
REFERENCES:
Pepin M et al.Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000 Mar 9;342(10):673-80.
Loeys BL et al.(2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788-98
Mizuguchi T et al. (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855-60
Stheneur C et al. (2008) Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat in Brief#1031,29:E284-E295
Guo DC, et al Am J Hum Genet. 2009 May:84(5):617-27. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.
Callewaert BL, et.al. Hum Mutat. 2008 Jan;29(1):150-8. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families.
Coucke PJ, et.al. Nat Genet. 2006 Apr;38(4):400-1. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome.
Van de Laar et al Nat Genet 43:121-126, 2011. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.