Pulmonary Arterial Hypertension

Preferred test to confirm a diagnosis of PAH, especially in those with a family history of PAH

Preferred test to confirm diagnosis or assess carrier status for an EIF2AK4-associated disorder such as pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD)

  • Recommended test if there is a known familial sequence variant previously identified in a family member
  • A copy of the family member’s lab report documenting the known familial variant is required

Pulmonary arterial hypertension (PAH) is caused by widespread occlusion or destruction of the smallest pulmonary arteries, leading to increased blood flow resistance, right ventricular hypertrophy, and heart failure. Genetic testing is most appropriate when no obvious etiology for pulmonary hypertension is found or if a family history of PAH exists.

Disease Overview

Symptoms

  • Shortness of breath
  • Fatigue
  • Syncope
  • Chest pain
  • Palpitations
  • Edema

Epidemiology 

Incidence: 1-2/million

Inheritance 

  • Autosomal dominant: ACVRL1, BMPR2, CAV1, ENG, KCNA5, KCNK3, and SMAD9 
  • Autosomal recessive: EIF2AK4

Test Description 

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

  • 75-80% for familial cases  
  • ~25% for simplex cases  

Limitations

  • A negative result does not exclude a heritable form of pulmonary arterial hypertension.
  • 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 genes
    • Regulatory region variants and deep intronic variants 
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in KCNA5
    • 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:
      • EIF2AK4 (NM_001013703) 2, 5, 29, 34, 35

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder PAH Attributable to Gene

ACVRL1

601284

HHT type 2

1%

BMPR2

600799

BMPR2-related PAH; PAH1; PVOD type 1

~75% of familial cases; ~25% of simplex cases

CAV1

601047

PAH3

~1%

EIF2AK4

609280

PVOD2

>10%

ENG

131195

HHT type 1

~1%

KCNA5

176267

Familial atrial fibrillation-7

Unknown

KCNK3

603220

PAH4

~1-3%

SMAD9

603295

PAH2

Unknown

HHT, hereditary hemorrhagic telangiectasia; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiotomatosis; PVOD, pulmonary veno-occlusive disease

References

Additional Resources