Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Polymerase Chain Reaction/Sequencing
- 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
Multiplex Ligation-dependent Probe Amplification
- Useful for confirming a diagnosis when a pathogenic deletion/duplication variant has been identified in family member
- A copy of the family member’s lab report documenting the 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
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
-
24951767
Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115(1):189-202.
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28768485
Garcia-Rivas G, Jerjes-Sánchez C, Rodriguez D, et al. A systematic review of genetic mutations in pulmonary arterial hypertension. BMC Med Genet. 2017;18(1):82.
GeneReviews - Heritable Pulmonary Arterial Hypertension
Austin ED, Loyd JE, Phillips JA III. Heritable pulmonary arterial hypertension. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last update: Jun 2015; Accessed: Feb 2020]
27770446
Ma L, Chung WK. The role of genetics in pulmonary arterial hypertension. J Pathol. 2017;241(2):273-280.
23883380
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361.
27443134
Prins KW, Thenappan T. World Health Organization group I pulmonary hypertension: epidemiology and pathophysiology. Cardiol Clin. 2016;34(3):363-374.
Genetic testing and counseling for idiopathic and familial PAH
Scientific Leadership Council. Genetic testing and counseling for idiopathic and familial pulmonary arterial hypertension (PAH). Pulmonary Hypertension Association. [Last revised: Nov 2008; Accessed: Nov 2018]
Preferred test to confirm a diagnosis of PAH, especially in those with a family history of PAH