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Pan Aortopathy and Connective Tissue Disorders Panel

The Pan Aortopathy and Connective Tissue Disorders Panel is a comprehensive next-generation (NGS) panel that can be used to confirm a clinical diagnosis of an inherited aortopathy or connective tissue disorder or identify at-risk individuals.

Aortopathies are disorders involving dysfunction of the aorta. The Pan Aortopathy and Connective Tissue Disorders panel includes genes related to isolated thoracic aortic aneurysms and dissections, as well as connective tissue disorders that have aortopathy as a feature. The connective tissue disorders included in this panel are Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and Marfan syndrome. Features of connective tissue disorders can include joint hypermobility, cutaneous findings, skeletal abnormalities, and cardiovascular issues. Individuals with isolated aortopathies and syndromic connective tissue disorders may be at risk for sudden death related to aortic aneurysm and dissection.

Included Disorders

This panel includes genes associated with:

  • Thoracic aortic aneurysms and dissections (TAAD)
  • Loeys-Dietz syndrome
  • Ehlers-Danlos syndrome
  • Marfan syndrome

Prevalence

The prevalence of various forms of aortopathies and connective tissue disorders are:

  • Ehlers-Danlos syndrome-1 in 20,000 individuals (Byers, 2001)
  • Loeys-Dietz syndrome- Unknown
  • Marfan syndrome- 1 in 5,000 to 1 in 10,000 individuals (Nijbroek et al, 1995)
  • Thoracic aortic aneurysms and dissections (TAAD)- Unknown

Inheritance and Penetrance

Ehlers-Danlos syndrome and related conditions are inherited in an autosomal dominant, autosomal recessive, and X-linked manners. Loeys-Dietz syndrome and Marfan syndrome are typically inherited in an autosomal dominant manner. Penetrance is typically high.

Isolated thoracic aortic aneurysms and dissections are typically inherited in an autosomal manner and exhibit reduced penetrance.

Clinical Sensitivity

A pathogenic variant can be identified in approximately 95% of Loeys-Dietz syndrome cases (Loeys and Dietz, 2008), 70-93% of Marfan syndrome cases (Arslan-Kirchner et al, 2011), and 50-90% of classic Ehlers-Danlos cases, and in 95% of vascular Ehlers-Danlos cases (Mayer et al, 2012). A pathogenic variant can be identified in approximately 30% of individuals with a family history of aortic aneurysm, who do not have a diagnosis of Marfan, Loeys-Dietz or Ehlers-Danlos syndromes (Milewicz and Regalado 2012).

Methodology and Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent flanking bases, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity and specificity of the assay is >99%.

Indications for Testing

  • Confirmation of a clinical diagnosis
  • Personal or family history of aortic aneurysm or dissection
  • Risk assessment for asymptomatic family members of proband with molecular diagnosis

Included Genes (32)

ACTA2 CHST14 COL5A1 FBN1 MED12 P3H1 SLC2A10 TGFB2
ADAMTS2 COL1A1 COL5A2 FBN2 MYH11 PLOD1 SLC39A13 TGFB3
ATP7A COL1A2 CRTAP FKBP14 MYLK PRKG1 SMAD3 TGFBR1
CBS COL3A1 EFEMP2 FLNA NOTCH1 SKI SMAD4 TGFBR2

 

Additions to Comprehensive Panel

Emerging evidence genes can also be added onto the Pan Aortopathy and Connective Tissue Disorders Panel. These genes do not have a clear association with aortopathies and connective tissue disorders, but emerging evidence suggests that they may play a role in disease pathogenesis.

Emerging Evidence Gene (2)

MAT2A SMAD6

 

References

  1. Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De Paepe A, Epplen J, Jondeau G, Loeys B, Faivre L. Clinical utility gene card for: Marfan syndrome type 1 and related phenotypes. Eur J Hum Genet. 2011;19(10) [FBN1]
  2. Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver, Beaudet, Sly, Valle, eds. The Metabolic and Molecular Bases of Inherited Disease. 2 ed. Edinburgh, UK: Churchill Livingstone; 2001:1065-81.
  3. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2013 Jul 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  4. Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlossyndrome types I-VII and variants – update 2012. Eur J Hum Genet. 2013;21(1)
  5. Milewicz D, Regalado E. 2012. Thoracic Aortic Aneurysms and Aortic Dissections. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle.
  6. Nijbroek, G., et.al. (1995). “Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons.” Am J Hum Genet 57(1): 8-21.