Mutations in several genes have been associated with an increased risk for aneurysm and dissection of the thoracic aorta and other major arteries. Depending on the gene, aneurysm may occur in the context of a recognizable genetic syndrome (e.g. Marfan syndrome or Loeys-Dietz syndrome) or with few to no additional clinical findings (a group of disorders known as familial thoracic aortic aneurysm and dissection, or familial TAAD). Identification of a patient’s underlying gene mutation can have significant implications for vascular screening and management. The following are some general considerations for clinicians who wish to order genetic testing.
Mutations in genes encoding components of the extracellular matrix, TGF-β signaling pathway, and vascular smooth muscle cell cytoskeleton have all been shown to cause both syndromic and non-syndromic forms of TAAD. In both syndromic and non-syndromic TAAD, the age of onset and presentation of aortic disease is variable.
Non-syndromic Familial TAAD
Approximately 20% of individuals with thoracic aortic aneurysm have a first-degree relative who is similarly affected, and are thus considered to have familial TAAD. This group includes individuals with aneurysm at the level of the sinuses of Valsalva, of the ascending aorta, and less commonly of the descending thoracic aorta. Dissection of the ascending thoracic aorta, descending thoracic aorta, or both, may occur.
Familial TAAD is mostly dominantly inherited, with variable expression and incomplete penetrance. Mutations in the ACTA2, MYH11. MYLK, and PRKG1 genes primarily result in TAAD. Mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, and FBN1 are mostly associated with syndromic forms of TAAD but may also result in non-syndromic TAAD (see table below).
Certain clinical findings in addition to aortic disease may also be present in this group, though their absence does not exclude the diagnosis of familial TAAD. Vascular findings beyond the thoracic aorta may be present, including most commonly:
- Aneurysms and dissections of peripheral arteries
- Patent ductus arteriosus
- Bicuspid aortic valve
- Premature stroke and/or coronary artery disease*
- Moyamoya disease*
Non-vascular clinical features that may also be present:
- Livedo reticularis*
- Iris flocculi*
*Primarily associated with mutations in ACTA2
Aortic aneurysm and dissection are a characteristic feature of several genetic syndromes. These include (but are not limited to) Marfan syndrome, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome type IV.
Marfan syndrome results from dominant mutations in FBN1, which encodes the protein fibrillin-1, an extracellular matrix protein that contributes to microfibril formation in elastic and non-elastic tissues. Aortic dilatation (commonly at the level of the sinuses of Valsalva) is common and can result in dissection, though presentation and age of onset is variable, and dilatation may be mild or absent in some individuals. Ectopia lentis (lens dislocation) is a characteristic feature of Marfan syndrome, and is present in approximately 60% of affected individuals. Other characteristic clinical findings include (but are not limited to) relative tall stature, arachnodactyly, chest wall deformity, dural ectasia, and mitral valve prolapse.
Loeys-Dietz syndrome is a genetically heterogeneous condition resulting from mutations in TGFBR1 or TGFBR2 (which encode the transforming growth factor-β receptors type 1 and 2, respectively), and less commonly from mutations in SMAD3 (which encodes the signal transduction mediator Mothers against decapentaplegic homolog 3) and TGFB2 (encoding TGFβ-2, a member of the TGFβ family of cytokines). Aortic root dilatation is frequent, and aneurysms and dissections can also occur in arteries other than the aorta. Arterial tortuosity is present in some affected individuals. Common musculoskeletal findings include joint laxity, joint contracture, chest wall deformity, scoliosis, and club foot. Cutaneous (translucent skin, easy bruising, wide scars) and craniofacial (hypertelorism, cleft palate/bifid uvula, craniosynostosis) features can also be variably present. Inheritance is autosomal dominant.
Ehlers-Danlos syndrome type IV
Ehlers-Danlos syndrome (EDS) type IV is a connective tissue disorder caused by a dominant mutation in COL3A1, which codes for the proα1(III) chains of type III collagen. This condition is characterized by increased risk for vascular dissection and rupture, bowel rupture, and uterine rupture during pregnancy. The thoracic aorta is not the most common site of vascular complications, though aneurysms, dissections, and rupture may occur. Thin skin with visible veins, easy bruising, small joint hypermobility, and characteristic facial features (thin nose, thin lips and philtrum, small chin, and large eyes) are common features.
Single gene testing vs. Multi-gene panels
Multi-gene panels offer a time efficient and cost-effective option in instances when the clinical evaluation is not suggestive of a specific single gene disorder. The underlying gene responsible for non-syndromic familial TAAD in a given patient or family is often not evident based on clinical evaluation alone. For such instances, a panel is the recommended approach.
Panels are also recommended for the patient or family whose clinical features are suggestive of a syndromic aortopathy but not specific enough to focus the search to a single gene. This is commonly encountered in the evaluation of a patient with overlapping features of Marfan syndrome and Loeys-Dietz syndrome.
The following table lists the genes available for clinical testing through the Collagen Diagnostic Lab and their associated phenotype(s):
MFS=Marfan syndrome, LDS=Loeys-Dietz syndrome,
EDS IV=Ehlers-Danlos syndrome type IV
A panel-based approach to genetic testing is not indicated if physical examination and evaluation of patient’s medical and family history are consistent with a known single gene disorder.
For more information about the familial aneurysm panels offered by the CDL, please see our test menu.
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