Aortopathy Panel, Sequencing and Deletion/Duplication

Aortopathy disorders are characterized by progressive aortic dilation, dissection, and other vascular findings, and may involve multiple organ systems. If an individual meets clinical criteria for a specific disorder (eg, Marfan syndrome [MFS], Ehlers-Danlos syndrome[EDS]) or if a specific diagnosis is suspected, consider more targeted gene testing first.

Disease Overview

Symptoms

• Aneurysm, dissection, and/or rupture of the aorta in any aortic section, including the aortic root or arch, ascending or descending aorta
• Cerebral, thoracic, and abdominal arterial aneurysms and/or dissections
• Skeletal manifestations, joint laxity, or craniofacial features

Etiology

Pathogenic variants in genes associated with aortopathy lead to structurally weakened cardiac, vascular, and/or connective tissues that become prone to progressive aneurysm, dissection, and/or rupture. Malformations of the heart, dysmorphic features, joint and skin laxity, and skeletal defects may also occur.

Prevalence

• MFS – 1/5,000-10,000
• Homocystinuria due to cystathionine beta-synthase deficiency (HCY) – 1/1,800-800,000
• EDS, type I/II (EDS I/II) – 1/20,000
• EDS, type IV (EDS IV) – at least 1/250,000
• Thoracic aortic aneurysm and dissection (TAAD) – 9 to 16/100,000 individuals/year; is familial in approximately 20 percent of cases

Inheritance

• Autosomal recessive for CBS, EFEMP2, PLOD1, and SLC2A10
• X-linked for FLNA
• Autosomal dominant for all other genes

Genotype-Phenotype Correlation

• Clinical phenotype may vary and overlap among disorders.
• Complete penetrance is seen in MFS, EDS IV, EDS VI, congenital contractoral arachnodactyly (CCA), and Loeys-Dietz syndrome (LDS), with rare exceptions.
• Reduced penetrance is seen in TAAD and EDS I/ II.
• May include previously undiagnosed Turner syndrome.

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Indications for Ordering

• Clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected
• If an individual meets clinical criteria for a specific disorder or if a specific diagnosis is suspected, consider more targeted gene testing first.

Limitations

• A negative result does not exclude a heritable form of MFS, HCY, EDS, TAAD, CCA, or LDS.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted gene(s)
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Deletions/duplications in LOX
  • Noncoding transcripts
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Deletions/duplications less than 1kb in the targeted genes by array
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Single exon deletions/duplications in the following exons:
    • COL3A1 (NM_000090) 6, 7, 9, 13; COL5A1 (NM_000093) 1, 16, 20; COL5A2 (NM_000393) 36; MYH11 (NM_001040113) 42; PRKG1 (NM_006258) 8, 17; TGFBR1 (NM_004612) 1

Analytical Sensitivity

For massively parallel sequencing:

Genes Tested