Figure 1
Discovery of gene mutations that caused heritable pulmonary arterial hypertension (PAH) began with the localization of a causative gene to chromosome 2 at the time of the 2nd World Symposium on Pulmonary Hypertension and continued as important scientific advances were reported at successive World Symposia on Pulmonary Hypertension (WSPH). Genes with mutations that cause PAH include BMPR2 (bone morphogenetic protein receptor type II), ALK1 (activin A receptor type II-like 1), ENG (endoglin), SMAD1 (mothers against decapentaplegic homologue 1), SMAD9 (mothers against decapentaplegic homologue 9), CAV1 (caveolin 1), KCNK3 (potassium channel subfamily K, member 3), TBX4 (T-box 4), and EIF2AK4 (eukaryotic translation initiation factor 2 α kinase 4). Reproduced with permission of the © ERS 2021: European Respiratory Journal Jan 2019, 53 (1) 1801899; DOI: 10.1183/13993003.01899-2018.16
Table 1
Genes with mutations reported to cause heritable pulmonary arterial hypertension (PAH). Adapted from Morrell NW et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019 Jan; 53(1). DOI: 10.1183/13993003.01899-2018.16 HHT: hereditary hemorrhagic telangiectasia; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary hemangiomatosis.
| GENE | PREVALENCE (%)* | PHENOTYPE | COMMENT |
|---|---|---|---|
| BMPR2 | 15.3 | PAH | Autosomal dominant with incomplete penetrance |
| TBX4 | 1.3 | PAH | Autosomal dominant with incomplete
penetrance More common in children |
| KCNK3 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| GDF2 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| KLF2 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| SMAD4 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| ATP13A3 | 1.1 | PAH | Autosomal dominant with incomplete penetrance |
| BMPR1B | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| KCNA5 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| SMAD1 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| SMAD9 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| SOX17 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| AQP | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| CAV1 | <1.0 | PAH | Autosomal dominant with incomplete penetrance |
| ACVRL1 | <1.0 | HHT | Autosomal dominant with incomplete penetrance |
| ENG | <1.0 | HHT | Autosomal dominant with incomplete penetrance |
| EIF2AK4 | <1.0 | PVOD, PCH | Autosomal recessive with complete penetrance |
Figure 2
A simple algorithm for genetic counseling followed by informed consent to perform genetic testing of patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) or familial pulmonary arterial hypertension (FPAH).
Table 2
Guidelines for genetic counseling.
| Describe disease characteristics, mutation detection techniques, and the inheritance pattern of disease transmission. |
| Describe potential implications of genetic test results for the patient. |
| Describe implications and possible consequences for the patient’s family members. |
| Describe prevention and treatment possibilities. |
| Obtain informed consent for genetic testing. |
| Provide individual consultation for asymptomatic high-risk relatives. |