Heritable Pulmonary Arterial Hypertension Overview
Hanabi Geiger, Rory J Tinker, MD, Janet Talbert, MS, CGC, John A Phillips, III, MD no PhD, and Eric D Austin, MD, MSCI.
Author Information and AffiliationsInitial Posting: July 18, 2002; Last Update: April 9, 2026.
Estimated reading time: 27 minutes
1. Clinical Characteristics of Heritable Pulmonary Arterial Hypertension
Heritable pulmonary arterial hypertension (HPAH) includes familial pulmonary arterial hypertension (PAH) (i.e., PAH that occurs in ≥2 family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant in one of the known PAH-associated genes has been identified [Levine 2021].
Note: Pulmonary hypertension (PH) is a general designation for increased blood pressure in the lungs from any cause and is classified into five groups by the World Symposium of PH (WSPH) [Simonneau et al 2019, Kovacs et al 2024]. PAH is classified as Group 1, and is a clinical diagnosis that is established by excluding the others, including PH resulting from heart disease (Group 2), PH resulting from lung disease or hypoxia (Group 3), PH from chronic thromboembolic disease (Group 4), and a variety of miscellaneous causes such as metabolic disorders, sarcoidosis, or splenectomy (Group 5). Group 1 PH (i.e., PAH) is a precapillary condition.
Clinical Manifestations
HPAH can develop in childhood to late adulthood. The initial symptoms of PAH are nonspecific and develop slowly (e.g., dyspnea, fatigue, chest pain, palpitations). Affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. The average time from symptom onset to diagnosis is 1.9 years [Badlam et al 2021]. The mean age at diagnosis of HPAH is 34.9 ± 14.9 years [Larkin et al 2012]. Some individuals report no symptoms, and diagnosis is suspected based on clinical identification of the following [Ntiloudi et al 2024]:
Accentuation of the pulmonic component of the second heart sound
Right ventricle (RV) heave, cardiac murmur such as tricuspid regurgitation resulting from RV dilatation, or diastolic murmur of pulmonary regurgitation
Signs of RV backward failure such as peripheral edema, distended jugular veins, ascites, hepatomegaly, and abdominal distention
Signs of RV forward failure such as cyanosis, pallor, cool extremities, and prolonged capillary refill
Clinical Testing to Confirm PAH
The approach to the individual with suspected PAH is described by several international guidelines [Galiè et al 2016, Humbert et al 2022, Ruopp & Cockrill 2022]. When possible, evaluation at a center that specializes in PH is recommended. Once symptoms or signs concerning for PAH are identified on clinical exam, the following evaluations are recommended [Ntiloudi et al 2024]:
Electrocardiogram
Transthoracic echocardiogram
Cardiopulmonary exercise test (CPET)
Laboratory studies including complete blood count, comprehensive metabolic panel, brain natriuretic peptide (BNP), antinuclear antibody, Rh factor, HIV testing, and coagulation studies
Chest CT and consideration of ventilation/perfusion scan and pulmonary function studies
The diagnosis of PAH is established at the time of right heart catheterization (RHC) at rest, which is recommended for all individuals with suspected PAH.
Cardiac catheterization can be used to directly measure pulmonary artery pressures and exclude other cardiac abnormalities.
Challenge testing with vasodilators (i.e., inhaled nitric oxide), fluid loading, or both during catheterization is important to assess physiologic responses to guide appropriate therapy.
The severity of PAH is determined using the World Health Organization functional class, which relies on six-minute walking distance, CPET parameters, BNP or N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography, cardiac MRI, and hemodynamic parameters [Humbert et al 2022].
Prognosis
While females are more likely to be affected than males; they have a 48% lower risk of death compared to males [DesJardin et al 2024]. This is likely due to better baseline RV function and better responses to treatments like endothelin receptor antagonists and prostacyclins [Alturaif et al 2025]. There appears to be no female predominance in those with childhood onset [Takatsuki et al 2023].
The variability in survival across individuals is broad, ranging from sudden death to death decades after diagnosis (rare) [Ballard et al 2021]. Children have worse hemodynamic parameters than adults at diagnosis but similar post-diagnosis survival [Takatsuki et al 2023]. Untreated individuals gradually deteriorate, with a mean survival of 2.8 years following diagnosis.
2. Genetic Causes of Heritable Pulmonary Arterial Hypertension
To date, twelve genes associated with heritable pulmonary arterial hypertension (HPAH) have been classified with definitive evidence (ACVRL1, ATP13A3, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) and three genes with moderate evidence (ABCC8, GGCX, and TET2) [Welch et al 2023]. Table 1 lists the estimated percentage of HPAH caused by pathogenic variants in each of these genes based on data from 2,572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group 1 pulmonary arterial hypertension (PAH) (including 1,211 individuals with a clinical diagnosis of familial or idiopathic PAH prior to genetic testing) enrolled in the PAH Biobank [Zhu et al 2019].
Table 1.
Heritable Pulmonary Arterial Hypertension: Genes and Distinguishing Clinical Features
View in own window
| Gene 1 | MOI | % of Persons w/Pathogenic Variant in Gene | PAH Phenotype & Associated Features | Comment | Reference |
|---|
|
ABCC8
| AD | 1% | Isolated PAH |
|
Welch et al [2023]
|
|
ACVRL1
| AD | <1% 3 | PAH-HHT |
| OMIM 600376, Welch et al [2023] |
|
ATP13A3
| AR
AD | <1% | PAH |
| OMIM 265400, Welch et al [2023] |
|
BMPR2
| AD | ~75%
(8% in US PAH Biobank) |
|
| OMIM 178600, OMIM 265450, Cogan et al [2006], Welch et al [2023] |
|
CAV1
| AD | <1% 3 | Isolated PAH |
| OMIM 615343, Welch et al [2023] |
|
EIF2AK4
| AR | <1% |
|
| OMIM 234810, Welch et al [2023] |
|
ENG
| AD | <1% 3 |
|
| OMIM 187300, Welch et al [2023] |
|
GDF2
| AD | <1% | Isolated PAH PAH-HHT PAH w/AVMs
|
| OMIM 615506, Welch et al [2023] |
|
GGCX
| AD | <1% | Isolated PAH |
|
Welch et al [2023]
|
|
KCNK3
| AD | <1%-3% 3 | Isolated PAH |
| OMIM 615344, Welch et al [2023] |
|
KDR
| AD | <1% 3 | Isolated PAH |
| Swietlik et al [2020], Welch et al [2023] |
|
SMAD9
| AD | <1% 3 | Isolated PAH PAH-HHT PAH w/pulmonary AVMs
|
| OMIM 615342, Welch et al [2023] |
|
SOX17
| AD | <1% | Isolated PAH | To date, 1 large del reported 2 | OMIM 612248, Welch et al [2023] |
|
TBX4
| AD | <1% 3 | Ischiopatellar dysplasia (small patella syndrome), TBX4-related (TBX4 syndrome) |
| OMIM 147891, Welch et al [2023] |
|
TET2
| AD | <1% 3 | Isolated PAH |
| Potus et al [2020], Welch et al [2023] |
- 1.
Genes are listed alphabetically.
- 2.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
- 3.
Molecular genetic testing of 2,572 individuals with Group 1 PAH identified a pathogenic variant in ACVRL1 (16 individuals), CAV1 (10), ENG (6), KCNK3 (3), KDR (4), SMAD9 (13), TBX4 (23), and TET2 (10) [Zhu et al 2019].
- 4.
In a retrospective study, the records of all individuals with a diagnosis of fenfluramine-associated PAH evaluated from 1986 to 2004 were studied. The median duration of fenfluramine exposure was six months, with a median of 4.5 years between exposure and onset of symptoms of PAH. Of those tested, nine (22.5%) of the 40 persons evaluated had a BMPR2 pathogenic variant [Souza et al 2008].
- 5.
Lifetime risk of PAH in those with a BMPR2 PAH-related loss-of-function variant is 14% in males and 42% in females.
3. Differential Diagnosis of Heritable Pulmonary Arterial Hypertension
Other cardiopulmonary causes of pulmonary hypertension (PH) are far more common than pulmonary arterial hypertension (PAH). Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include connective tissue diseases, autoimmune disorders, cirrhosis, HIV infection, treatment with appetite suppressants, and the following acquired and hereditary disorders [Badesch et al 2010, Jones et al 2022, Guignabert et al 2024, Kovacs et al 2024]:
Heart disease (World Symposium on Pulmonary Hypertension [WSPH] Group 2). Most advanced cardiac conditions, including left ventricular dysfunction,
congenital heart disease, valvular disease, and cardiomyopathy, can cause PH. Heart diseases are detected by physical examination, electrocardiogram, echocardiogram, and cardiac catheterization.
Lung disease or hypoxia (WSPH Group 3). The advanced stages of all lung diseases may cause PH. Most lung diseases that cause PH are identified by detection of abnormal lung sounds on physical examination, pulmonary function testing, and/or high-resolution chest CT.
Pulmonary embolism / disease of large pulmonary vessels (WSPH Group 4). Pulmonary embolism or disease of large pulmonary vessels is detected by imaging procedures, traditionally by screening by lung perfusion scanning with confirmation by pulmonary arteriography. Although CT angiography has improved greatly, nuclear medicine perfusion scanning still has a role in screening for chronic thromboembolic pulmonary hypertension (CTEPH), a disorder in which pulmonary emboli are not resorbed normally by fibrinolysis. It is important to correctly diagnose CTEPH because surgical pulmonary thromboendarterectomy is highly effective under the appropriate medical circumstances [
Yang et al 2023].
Acquired pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
4. Evaluation Strategies to Identify the Genetic Cause of Heritable Pulmonary Arterial Hypertension in a Proband
The diagnosis of heritable pulmonary arterial hypertension (HPAH) is established in a proband with identification of all of the following [Humbert et al 2022]:
Confirmation of the presence of PAH (i.e., mean pulmonary artery pressure >20 mm Hg at rest during right heart catheterization [RHC] [
Simonneau et al 2019])
Identification of a
heterozygous pathogenic (or
likely pathogenic) variant(s) in one of the genes known to be associated with HPAH (see
Table 1) and/or confirmation of PAH in one or more of the
proband's family members
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "
pathogenic variant" and "
likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Richards et al 2015]. Reference to "pathogenic variants" in this
GeneReview is understood to include likely pathogenic variants. (2) Identification of a
heterozygous variant of
uncertain significance in one of the genes known to be associated with HPAH does not establish or rule out the diagnosis.
Establishing a specific genetic cause of HPAH:
Can aid in discussions of prognosis (which are beyond the scope of this
GeneReview) and
genetic counseling;
Medical history and physical examination. No particular findings in the medical history or on physical examination distinguish among most genetic causes of HPAH. However, skeletal anomalies (e.g., patellar irregularities), tracheal and/or bronchial diverticulosis on CT or bronchoscopy, developmental delay, and congenital heart disease can be suggestive of ischiopatellar dysplasia, TBX4-related [Austin & Elliott 2020]. PAH in those with ischiopatellar dysplasia, TBX4-related is associated with younger onset, better performance on the six-minute walking test, worse pulmonary function testing, higher frequency of airway abnormalities, and longer event-free survival [Mullen 2022].
Family history. A three-generation family history should be taken, with attention to relatives with manifestations of HPAH and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, serial single-gene deletion/duplication analysis) and comprehensive
genomic testing (exome sequencing, genome sequencing, chromosome microarray). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).
Option 1
A multigene panel that includes the genes listed in Table 1 is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Serial single-gene deletion/duplication analysis. Gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Option 2
Comprehensive
genomic testing does not require the clinician to determine which genes are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. Genome sequencing may detect noncoding variants missed by exome sequencing (e.g., deep intronic splice variants, variants in untranslated regions, and copy number variants).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including BMPR2 and ENG) that cannot be detected by sequence analysis.
Genetic Modifiers
Sequence analysis for RNF213 variants associated with resistance to treatment can be considered for individuals with more severe manifestations that are resistant to treatment [Ruopp & Maron 2020].
5. Management of Heritable Pulmonary Arterial Hypertension
Treatment of Manifestations
Targeted Therapies
In GeneReviews, a targeted therapy
is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED
Targeted therapies approved by the US Food and Drug Administration for adults with pulmonary arterial hypertension (PAH) are listed in Table 2 [Klinger et al 2019, Hassoun 2021, Ruopp & Cockrill 2022, Humbert et al 2023] (see FDA Orange Book). Treatment preference of route of medication administration (e.g., continuous intravenous, subcutaneous, aerosol, oral) and possible side effects determine which agents are personally acceptable for the affected individual.
Table 2.
Heritable Pulmonary Arterial Hypertension: Targeted Therapies
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| Treatment | Mechanism of Action | Considerations |
|---|
| Sildenafil | Selective inhibition of PDE-5 in pulmonary vascular smooth muscle, which leads to increased intracellular cGMP & subsequent vasodilation | Does not require blood monitoring May cause headache, skin flushing, diarrhea, or nasal congestion. Priapism is a rare adverse event.
|
| Bosentan | Antagonizes endothelin A & B receptors & blocks effects of endothelin-1 (a potent vasoconstrictor & promoter of vascular remodeling) | Requires blood monitoring due to hepatoxicity May cause anemia & systemic vasodilation 1 Other ERAs have reduced hepatotoxicity. Pregnant persons should not take or touch ERAs.
|
| Epoprostenol | Prostacyclin & prostacyclin analog class of medications Activates prostacyclin receptor (IP) on pulmonary vascular smooth muscle cells, leading to increased cAMP, which causes potent vasodilation Also inhibits smooth muscle proliferation & exerts antithrombotic & anti-inflammatory effects
| Most effective treatment available Short half-life; delivered by continuous IV pump Common side effects include headache, jaw pain, & nausea. Requires monitoring for systemic vasodilation & complications of continuous IV drug delivery (e.g., sepsis related to central venous catheter) 2
|
cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; ERA = endothelin receptor antagonist; IP = prostaglandin I2 receptor; IV = intravenous; PDE-5 = phosphodiesterase type 5
- 1.
- 2.
Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields. For pediatric care, Abman et al [2015] and Hansmann et al [2019] provide evidence-based treatment algorithms for care. For adult-focused care, multiple publications provide evidence-based treatment algorithms, including Humbert et al [2023].
Referral centers specializing in diagnosis and therapy of PAH are available across the US (see Pulmonary Hypertension Association, Find A PH Care Center). Consultation is encouraged for all individuals suspected of having PAH because of the complexity and continuing evolution of diagnosis and treatment.
Surveillance
To monitor for emergence of heritable pulmonary arterial hypertension (HPAH) in at-risk individuals, progression of disease, and treatment adjustment, the evaluations summarized in Table 4 are recommended.
Table 4.
Heritable Pulmonary Arterial Hypertension: Recommended Surveillance for Individuals with a Known Pathogenic Variant Associated with PAH
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| System/Concern | Evaluation | Frequency |
|---|
| PAH | Clinical eval | Annually in asymptomatic persons w/known PV assoc w/HPAH 1 |
| Echocardiogram |
|
| Cardiac catheterization | As needed for those w/abnormal findings on exam or echocardiogram |
HPAH = heritable pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; PV = pathogenic variant
- 1.
Agents/Circumstances to Avoid
Exercise precautions. Most clinicians recommend supervised exercise training as part of integrated PAH care, due to improvements in exercise capacity, quality of life, and functional status, with a low risk of serious adverse events when performed in specialized settings. Exercise programs typically combine aerobic and resistance training and may include respiratory muscle training and education [Klinger et al 2019, Rochester et al 2023]. Individuals with PAH should be monitored and start with low- to moderate-intensity aerobic exercise; this can be gradually progressed as tolerated. Those individuals with severe hemodynamic profiles or history of syncope/presyncope require close monitoring, often including telemetry. Exercise should immediately cease if symptoms such as severe dyspnea, chest pain, or presyncope occur. Forced exercise experiences for which the individual may not have the ability to control their effort or stop and rest should be avoided.
Medications. Individuals with PAH should avoid and/or discuss with a PAH specialist prior to using stimulant medications, recreational drugs such as cocaine or amphetamines, and certain other cardiopulmonary medications. Additional medications may need to be avoided; consider review of medications with a PAH specialist prior to using. In addition, drug-drug interactions should be carefully reviewed given the polypharmacy needs of many individuals [Wu et al 2022].
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of surveillance (see Table 4) and treatment (see Table 2) for those identified with PAH. Evaluations can include:
* Genetic testing of asymptomatic family members should be performed by a genetic counselor / medical geneticist and should include discussion of disease surveillance, treatment options, and prognosis with treatment [Austin et al 2024].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Pregnancy in individuals with PAH is generally contraindicated due to high maternal and fetal mortality, but outcomes have improved with multidisciplinary care and individualized management at specialized centers.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
6. Genetic Risk Assessment
Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.
Clarification of the genetic status of first-degree family members of an individual with heritable pulmonary arterial hypertension (HPAH) can allow early detection of HPAH and prompt initiation of treatment and improve long-term outcome. A basic view of HPAH genetic risk assessment is presented in this section; issues that may be specific to a given family or genetic cause of HPAH (e.g., pulmonary arterial hypertension [PAH] associated with hereditary hemorrhagic telangiectasia) are not comprehensively addressed.
Note: Given the complexity of the genetics and surveillance recommendations for HPAH, health care providers should consider referring at-risk asymptomatic relatives to a pulmonary hypertension specialty referral center (see Pulmonary Hypertension Association, Find A PH Care Center), or to a cardiovascular genetics center or genetic counselor specializing in cardiac or cardiopulmonary genetics (see NSGC – Find a Genetic Counselor).
Risk to Family Members – Autosomal Dominant Inheritance
Parents of a proband
Some individuals diagnosed with HPAH have the disorder as the result of a
de novo pathogenic variant. The proportion of individuals with HPAH caused by a
de novo pathogenic variant is unknown.
If a molecular diagnosis has been established in the
proband and the proband appears to be the only affected family member (i.e., a
simplex case),
molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform
recurrence risk assessment, and assess their need for cardiac surveillance for manifestations of HPAH (see
Surveillance).
Note: A
proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced
penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore,
de novo occurrence of an HPAH-related
pathogenic variant cannot be confirmed unless
molecular genetic testing has demonstrated that neither parent has the HPAH-related pathogenic variant.
If the
pathogenic variant identified in the
proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The
proband inherited a
pathogenic variant from a parent with gonadal (or somatic and gonadal)
mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of
somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Sibs of a proband. The risk to sibs of the proband depends on the clinical/genetic status of the proband's parents:
If a parent of the
proband is affected and/or is known to have the HPAH-related
pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Because of the significant possibility of reduced
penetrance of PAH in an individual who is
heterozygous for an HPAH-related
pathogenic variant (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the
proband may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known
BMPR2 pathogenic variant will express PAH clinically in their lifetime [
Larkin et al 2012].
If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a
proband with a known HPAH-related
pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see
Surveillance).
Offspring of a proband. Each child of an individual with an HPAH-related pathogenic variant is at a 50% risk of inheriting the pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or known to have an HPAH-related pathogenic variant, the parent's family members may be at risk.
Risk to Family Members – Autosomal Recessive Inheritance
Parents of a proband
If a
pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the
proband occurred as a
de novo event in the proband or as a
postzygotic de novo event in a mosaic parent [
Jónsson et al 2017]. If the proband appears to have
homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
Heterozygous parents of a
proband with
EIF2AK4-related HPAH are not at risk of developing
EIF2AK4-related HPAH. Heterozygous parents of a proband with
autosomal recessive ATP13A3-related HPAH may be at risk of PAH, although further study is needed to confirm this concern.
Sibs of a proband
If both parents are known to be
heterozygous for an
autosomal recessive HPAH-related
pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the
familial pathogenic variants.
Heterozygous sibs of a
proband with
EIF2AK4-related HPAH are not at risk of developing
EIF2AK4-related HPAH. Heterozygous sibs of a proband with
autosomal recessive ATP13A3-related HPAH may be at risk of PAH, although further study is needed to confirm this concern.
Offspring of a proband. The offspring of an individual with autosomal recessive HPAH are obligate heterozygotes (carriers) for an HPAH-related pathogenic variant.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HPAH-related pathogenic variant.
Carrier detection. Carrier testing for at-risk relatives requires prior identification of the HPAH-related pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the HPAH-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
PHAWARE
Pulmonary Hypertension Association (PHA)
Phone: 800-748-7274; 301-565-3004
American Heart Association
American Lung Association
Phone: 800-586-4872
MedlinePlus
Chapter Notes
Author Notes
Genetic and genomic discovery efforts in pulmonary arterial hypertension (PAH) are rapidly progressing. Some sites of interest include the following:
Pulmonary Hypertension Clinical & Research Team
Vanderbilt Research Registry of PAH Families, Idiopathic PAH Cases, and Other PAH Forms
Kelly Fox Burke, Coordinator
Vanderbilt University Medical Center
Phone: 800-288-0378
Email: gro.cmuv@ekrub.yllek
Acknowledgments
The authors – and the entire field – are indebted to the commitment and efforts of so many affected individuals, families, and researchers who have propelled the genetics of PAH forward. While it is risky to list names for fear of omission, at a minimum we thank the following:
The countless affected individuals, families, and related individuals who graciously participate in genetic studies of PAH across the world
John Newman, MD, and James Loyd, MD, who pioneered research on humans with PAH in their families at Vanderbilt
Lisa Wheeler, former Coordinator of Heritable PAH efforts at Vanderbilt
Kelly Burke, current Coordinator of Heritable PAH efforts at Vanderbilt
The countless collaborative research teams who work tirelessly to study PAH across the world
Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic
Author History
Eric D Austin, MD, MSCI (2015-present)
Hanabi Geiger (2026-present)
James E Loyd, MD; Vanderbilt University Medical Center (2002-2026)
John A Phillips, III, MD, PhD (2002-present)
Janet Talbert, MS, CGC (2026-present)
Rory J Tinker , MD (2026-present)
Revision History
9 April 2026 (sw) Comprehensive update posted live
23 December 2020 (ha) Comprehensive update posted live; scope changed to overview
11 June 2015 (me) Comprehensive update posted live
29 March 2011 (me) Comprehensive update posted live
18 July 2007 (me) Comprehensive update posted live
2 November 2004 (me) Comprehensive update posted live
18 July 2002 (me) Review posted live
14 January 2002 (jl) Original submission
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