Genetic Biomarkers in Aortopathy

Abstract

The field of aortopathy, in common with other genomic disorders, is undergoing a revolution. This is largely driven by the implementation of newer forms of genetic sequencing (massively parallel or next-generation sequencing). Advantages conferred by this technology include reduced costs, reduced sequencing time and the ability to simultaneously test multiple genes. This has a significant advantage in the identification of genes disrupted in heritable aortopathies. These advances are enabling scientists and clinicians to identify key molecular pathways; translating fundamental genetic findings into a better understanding of disease mechanisms is ultimately leading to effective treatments. In outlining contemporary knowledge of genetic biomarkers in aortopathy we seek to demonstrate that the era of genomically orientated decision-making is here.

The Genetics of Aortopathies in Clinical Cardiology

“…Familial TAAD (FTAAD) denotes a group of nonsyndromic disorders which generally present with isolated TAAs, without associated characteristic systemic features. Advances in next-generation sequencing are rapidly uncovering novel genes and/or loci associated with hereditary TAAs 7. Most genetic causes of heritable TAA disorders are inherited as monogenic defects with an autosomal dominant pattern of inheritance with high penetrance 7.…”

“…Advances in next-generation sequencing are rapidly uncovering novel genes and/or loci associated with hereditary TAAs 7. Most genetic causes of heritable TAA disorders are inherited as monogenic defects with an autosomal dominant pattern of inheritance with high penetrance 7. Altogether, genetic triggers account for about 20% of thoracic aortic disease; however, this is likely an underestimate due to underdiagnosis of silent TAAs in family members of probands and infrequent use of genetic testing in the clinical setting 1,8,10.…”

“…The defect results in friable aortic tissue with tears along the aorta and its branches, leading to rupture and dissection often without prerequisite aneurysm and high surgical mortality 7,39…”

“…Isolated TAAs are discovered in 11% to 19% of first-degree relatives of patients with TAAs, although the true rate may be higher due to undiscovered aneurysms 38. Although by definition, “isolated” TAAD occurs in the absence of other manifestations, many affected families do have identifiable extra-aortic features 7. Causative mutations in the following genes have been associated with FTAAD: smooth muscle–specific α-actin (ACTA2), vascular smooth muscle contractile protein β-MHC (MYH11), TGFBR2, myosin light chain kinase (MYLK), and a type 1 cyclic guanosine monophosphate–dependent protein kinase that controls smooth muscle relaxation (PRKG1) 3,42…”

“…These aneurysms likely arise from complicated interactions of multiple predisposing genes and environmental risk factors 2. In contrast, thoracic aortic aneurysms occur in all age groups and are more likely to be associated with a genetic background, presenting as either part of a syndromic disorder or an isolated aberration 2,7. In addition, TAAs may occur as a sporadic phenomenon or as a familial disorder; the latter may follow classic Mendelian inheritance or nonclassic inheritance of a complex trait 2,8.…”