Can a GeneDx (Genetic Diagnostic) Clinical Exome Sequence Analysis detect gene defects associated with ascending aorta dilatation and/or connective tissue disorders or familial aortopathies?

GeneDx Clinical Exome Sequence Analysis for Detecting Gene Defects in Aortopathies

Yes, GeneDx Clinical Exome Sequence Analysis can effectively detect gene defects associated with ascending aorta dilatation, connective tissue disorders, and familial aortopathies, as it would examine the key genes implicated in these conditions including FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, and MYH11. 1

Genetic Basis of Aortic Dilatation

• Thoracic aortic aneurysms and dissections (TAAD) have significant genetic heterogeneity, with multiple genes capable of causing similar clinical presentations 2
• The most common genetic causes of ascending aortic dilatation include:
  • Marfan syndrome (FBN1 mutations) 1
  • Loeys-Dietz syndrome (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 mutations) 1
  • Vascular Ehlers-Danlos syndrome (COL3A1 mutations) 1
  • Non-syndromic familial thoracic aortic aneurysms and dissections (FTAAD) (ACTA2, MYH11, MYLK mutations) 2, 1

Exome Sequencing for Aortopathies

• Exome sequencing is particularly valuable for aortopathies due to their genetic heterogeneity 3
• This approach can identify:
  • Known pathogenic variants in established genes (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) 2, 1
  • Novel variants in genes associated with aortic dilatation 3, 4
  • Potential genetic modifiers that influence disease severity 3

Clinical Utility of Genetic Testing

• Genetic testing helps identify the underlying cause of aortic dilatation, which has important implications for:
  • Risk stratification - certain genetic variants (e.g., TGFBR2) are associated with aortic dissection at smaller diameters (<5.0 cm) 2
  • Surgical timing - patients with specific genetic disorders may require earlier surgical intervention 2
  • Family screening - once a pathogenic mutation is identified, only relatives with the same mutation need regular aortic imaging 2, 1

Specific Genes Detectable by Exome Sequencing

• ACTA2 - recommended for sequencing in patients with family history of thoracic aortic aneurysms/dissections (Class IIa recommendation) 2
• TGFBR1, TGFBR2, MYH11 - may be considered for sequencing in patients with appropriate clinical features (Class IIb recommendation) 2
• FBN1 - associated with Marfan syndrome 2, 1
• COL3A1 - associated with vascular Ehlers-Danlos syndrome 1
• Additional genes like PRKG1 have been identified in cases of early-onset thoracic aortic disease 4

Limitations and Considerations

• Not all genetic causes of aortic dilatation have been identified - approximately 20% of familial cases have an identifiable genetic cause 3, 5
• Some complex or polygenic forms of aortic disease may be more challenging to diagnose 2, 5
• The differential diagnosis in patients with aortic dilatation is broad and includes many conditions outside the common connective tissue disorder spectrum 5

Clinical Recommendations

• For patients with thoracic aortic aneurysm/dissection, genetic evaluation should be considered to assist in diagnostic evaluation 5
• If a pathogenic mutation is identified, first-degree relatives should undergo counseling and testing 2
• Patients with genetic aortopathies require specialized monitoring and management, including regular imaging and potentially earlier surgical intervention 1