Clinical Information

Inherited forms of aortic disease, or aortopathies, may be associated with isolated thoracic aortic aneurysms and dissections or conditions with multi-system involvement. This gene panel includes genes for multiple conditions that may have aortopathy as a feature, including Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, arterial tortuosity syndrome, and heritable thoracic aortic disease (also known as familial thoracic aortic aneurysm/dissection: FTAAD). Other heritable conditions with overlapping clinical presentations are also covered by this panel. Confirming a genetic diagnosis in the setting of aortopathy may aid in differentiating the genetic etiology of complex or ambiguous clinical presentations, treatment decisions, and genetic counseling.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder affecting the connective tissue that occurs in approximately 1 to 2 per 10,000 individuals. It is characterized by the presence of skeletal, ocular, and cardiovascular manifestations and is caused by variants in the FBN1 gene. Skeletal findings may include tall stature, chest wall deformity, scoliosis, and joint hypermobility. Lens dislocation (ectopia lentis) is the cardinal ocular feature with mitral valve prolapse and aortic root dilatation/dissection the main cardiovascular features.(1)

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disease with significant overlap with Marfan syndrome but may include involvement of other organ systems and is primarily caused by variants in TGFBR1 and TGFBR2.(2,3) Features of LDS that are not typical of MFS include craniofacial and neurodevelopmental abnormalities and arterial tortuosity with increased risk for aneurysm and dissection throughout the arterial tree. Variants in the SMAD3 gene have been reported in families with an LDS-like phenotype with arterial aneurysms and tortuosity and early onset osteoarthritis. Variants in the TGFB3 gene have also been reported in families with an LDS-like phenotype, although these individuals tended to not have arterial tortuosity.

Heritable thoracic aortic disease (FTAAD) is a genetic condition primarily involving dilatation and dissection of the thoracic aorta but may also include aneurysm and dissection of other arteries. This condition has a highly variable age of onset and presentation and may involve additional features such as congenital heart defects and other features of connective tissue disease or smooth muscle abnormalities depending on the causative gene. The gene most commonly involved in FTAAD is ACTA2.(4,5)

Vascular Ehlers-Danlos syndrome (also known as vEDS or EDS IV) is an autosomal dominant connective tissue disease caused by variants in the COL3A1 gene. vEDS may present with characteristic facial features, thin, translucent skin, easy bruising, and arterial, intestinal, and uterine fragility. Arterial rupture may be preceded by aneurysm or dissection or may occur spontaneously.(6) Classic Ehlers-Danlos syndrome types I and II (also known as cEDS) are caused by variants in the COL5A1 and COL5A2 genes. Aortic root dilation and, more rarely, spontaneous vessel rupture have been reported in cEDS.(7)

Other genes included on this panel cause conditions with clinical overlap with those above. Examples include genes associated with rare, autosomal recessive forms of Ehlers-Danlos syndrome, the FLNA gene associated with periventricular nodular heterotopia, the FBN2 gene associated with congenital contractural arachnodactyly, the CBS gene associated with homocystinuria, the SLC2A10 gene associated with autosomal recessive arterial tortuosity syndrome, and the NOTCH1 gene associated with aortic valve disease and severe valve calcification. Currently, expert consensus indicates NOTCH1 variants may be predictive of thoracic aortic enlargement without evidence of progression to aortic dissection.(8-12)