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. 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. 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.

Genetics

Genes

See the Genes Tested table for genes included in the panel.

Prevalence

• MFS: 1/5,000-10,000
• Homocystinuria due to cystathionine beta-synthase deficiency (HCY): 1/1,800-335,000
• EDS, classic type (cEDS, type I/II): 1/20,000
• EDS, vascular type (vEDS, type IV): at least 1/200,000
• Thoracic aortic aneurysm and dissection (TAAD): 9-16/100,000 individuals/year; is familial in approximately 20% of cases

Inheritance

• Commonly autosomal dominant
• Autosomal recessive for CBS, EFEMP2, PLOD1, and SLC2A10
• X-linked for BGN and FLNA

Penetrance

• Complete penetrance is seen in MFS, vEDS, PLOD1-related kyphoscoliotic EDS (kEDS), congenital contractural arachnodactyly (CCA), and Loeys-Dietz syndrome (LDS), with rare exceptions.
• Reduced penetrance is seen in TAAD and cEDS.

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

• Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
• Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
• Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
• Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Analytic Sensitivity

For massively parallel sequencing:

Limitations

• A negative result does not exclude a heritable aortopathy disorder.
• 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 and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Deletions/duplications in TGFB3
  • The following regions are not sequenced due to technical limitations of the assay:
    • CBS (NM_001321072) exon(s) 1
    • COL5A1 (NM_000093) exon(s) 1
    • COL5A1 (NM_001278074) exon(s) 1
    • FOXE3 (NM_012186) partial exon(s) 1(Chr1:47882098-47882163)
• The following may not be detected:
  • Deletions/duplications/insertions of any size by MPS
  • Large duplications less than three exons in size
  • Noncoding transcripts
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Single-exon deletions/duplication in the following exons:

  • Gene	Exon(s)
    CBS	(NM_001321072) 1
    COL1A2	(NM_000089) 3
    COL5A1	(NM_000093) 1
    COL5A1	(NM_001278074) 1
    MYLK	(NM_053025) 13
    MYLK	(NM_001321309) 12
    MYLK	(NM_053026) 12
    MYLK	(NM_053027) 13
    MYLK	(NM_053028) 12
    NOTCH1	(NM_017617) 1

Genes Tested