Diagnostics

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Pan Pulmonary Hypertension Panel

The Pulmonary Hypertension Pan Panel is a comprehensive next-generation (NGS) panel that can be used to confirm a clinical diagnosis of pulmonary arterial hypertension or hereditary hemorrhagic telangiectasia.

Pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia are circulatory conditions that result in increased pressure in blood vessels.

Pulmonary arterial hypertension is a condition characterized by high blood pressure in the pulmonary artery caused by a narrowing of blood vessels in the lungs. Increased pressure in the pulmonary artery can cause increased pressure in and damage to, the right ventricle of the heart. Over time, pulmonary hypertension can cause dyspnea, syncope, chest pain, palpitations, and eventually progressive heart failure.

Hereditary hemorrhagic telangiectasia is a condition characterized by circulatory system abnormalities called arteriovenous malformations, which occur when arteries flow directly into veins, rather than into capillaries. These malformations result in increased pressure in affected blood vessels, which can result in episodes of severe bleeding. One of the most common symptoms of hereditary hemorrhagic telangiectasia is nosebleeds. Hemorrhages that occur in the brain, liver, lungs, or other organs can be life-threatening.

Included Disorders

This panel includes genes associated with:

  • Pulmonary arterial hypertension
  • Hereditary hemorrhagic telangiectasia
  • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Prevalence

The prevalence of hereditary hemorrhagic telangiectasia is between 1 in 5,000 to 1 in 8,000 individuals (Giovani and Shovlin, 2009), while the prevalence of pulmonary arterial hypertension in unknown.

Inheritance and Penetrance

Hereditary hemorrhagic telangiectasia is inherited in an autosomal dominant manner, and exhibits age-related penetrance and variable expressivity (McDonald and Pyeritz, 2000). Pulmonary arterial hypertension is inherited in an autosomal dominant manner, and exhibits reduced penetrance. The penetrance of pathogenic variants in BMPR2 has been estimated as 14-42% (Larkin et al, 2012).

Clinical Sensitivity

Pathogenic variants can be identified in more than 80% of hereditary hemorrhagic telangiectasia cases (Prigoda et al, 2006), and in approximately 75% of pulmonary arterial hypertension cases (Austin et al, 2002). The Pulmonary Hypertension Pan Panel includes all of the most common genes associated with these conditions.

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
  • Risk assessment for asymptomatic family members of proband with molecular diagnosis

Included Genes (7)

ACVRL1 BMPR2 CAV1 ENG RASA1 SMAD4 SMAD9

 

Additions to Comprehensive Panel

Emerging evidence genes can also be added onto the Pulmonary Arterial Hypertension Pan Panel. These genes do not have a clear association with pulmonary arterial hypertension or hereditary hemorrhagic telangiectasia, but emerging evidence suggests that they may play a role in disease pathogenesis.

Emerging Evidence Genes (4)

BMPR1B GDF2 KCNA5 KCNK3

 

References

  1. Austin ED, Loyd JE, Phillips JA III. Heritable Pulmonary Arterial Hypertension. 2002 Jul 18 [Updated 2015 Jun 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17(7):860-71.
  3. Larkin EK, Newman JH, Austin ED, et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(9):892-6.
  4. McDonald J, Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. 2000 Jun 26 [Updated 2017 Feb 2]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  5. Prigoda NL, Savas S, Abdalla SA, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet. 2006;43(9):722-8.