NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Heritable Pulmonary Arterial Hypertension Overview

, MD, MSCI, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: December 23, 2020.

Estimated reading time: 15 minutes

Summary

The purpose of this overview is to increase the awareness of clinicians regarding genetic causes of heritable pulmonary arterial hypertension (HPAH) and related genetic counseling issues.

The goals of this overview are the following:

Goal 1.

Describe the clinical characteristics of HPAH.

Goal 2.

Review the genetic causes of HPAH.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of HPAH in a proband (when possible).

Goal 4.

Inform genetic risk assessment and surveillance of at-risk relatives for detection of early treatable manifestations of HPAH.

Goal 5.

Review a high-level view of management of HPAH.

1. Clinical Characteristics of Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (HPAH) includes familial 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 genes has been identified.

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]. PAH is classified as Group 1, and it 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 PH (Group 4), and a variety of miscellaneous causes, metabolic disorders, sarcoidosis, or splenectomy (Group 5).

The diagnosis of HPAH is established clinically [Morrell et al 2019] by the following in a proband:

Clinical Symptoms

Clinical symptoms of HPAH include dyspnea, fatigue, chest pain, palpitation, syncope, or edema. HPAH affects all ages, including the very young and the elderly; the mean age at diagnosis is 34.9±14.9 years [Larkin et al 2012].

Females are twice as likely to be affected as males; survival is worse in males than in females [Kozu et al 2018].

The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across individuals is broad, ranging from sudden death to decades (rare). The physiologic stress of pregnancy in an individual with HPAH is significant and maternal mortality is believed to be substantial, with risk variable according to pulmonary arterial pressure and right ventricular dysfunction [Ballard et al 2021].

Clinical Examination

Because the symptoms of HPAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some individuals report no symptoms, and diagnosis is suspected on an incidental basis because of signs (abnormal findings on physical examination) including:

  • Accentuation of the pulmonic component of the second heart sound;
  • Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation;
  • Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course).

Clinical Testing to Confirm PAH

The approach to the individual with suspected PAH has been carefully described by several international guidelines [Galiè et al 2016]. Note: It is generally advised, when possible, to involve a specialty pulmonary hypertension referral center during the diagnostic work up.

Once symptoms or signs concerning for PAH are identified on clinical exam, the following evaluations are recommended:

  • Electrocardiogram
  • Transthoracic echocardiogram
  • Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies
  • Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies

Ultimately, the diagnosis of PAH is formally made at the time of cardiac catheterization at rest, which is recommended for all individuals with suspected PAH.

  • Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities.
  • Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy.

Differential Diagnosis of HPAH

Other cardiopulmonary causes of PH are far more common than 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, cirrhosis, HIV infection, treatment with appetite suppressants, and the following acquired and hereditary disorders [Badesch et al 2010]:

  • Heart disease (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, echocardiography, 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 computed tomographic lung imaging.
  • Pulmonary embolism / disease of large pulmonary vessels (WSPH Group 4). Pulmonary embolism or disease of large pulmonary vessels is detected by imaging procedures; traditionally, 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 [Kim et al 2013].
  • Acquired pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis. These conditions are typically acquired but may be hereditary on rare occasion (most often associated with biallelic pathogenic variants in EIF2AK4) [Best et al 2014, Eyries et al 2014].

2. Genetic Causes of Heritable Pulmonary Arterial Hypertension

To date, ten genes are convincingly known to be associated with heritable pulmonary arterial hypertension (HPAH), although more discoveries will likely emerge over the next few years. Table 1 lists the percentage of HPAH caused by pathogenic variants in each of these genes based on data from 2572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group1 PAH (including 1211 individuals with a clinical diagnosis of "familial" or "idiopathic" PAH prior to genetic testing) enrolled in the PAH Biobank as reported in Zhu et al [2019].

Of note:

  • BMPR2-releated HPAH is associated with decreased penetrance: lifetime risk of developing PAH with a BMPR2 pathogenic variant in a male is 14% and 42% in a female.
  • TBX4-related HPAH is associated with a variable phenotype with digit-limb-girdle abnormalities, developmental lung disease, developmental delay, and congenital heart disease, in addition to PAH (OMIM 147891).

Table 1.

Heritable Pulmonary Arterial Hypertension (HPAH): Genes and Distinguishing Clinical Features

Gene 1% of Individuals w/Pathogenic Variant in Gene 2Allelic DisordersReference
ACVRL1Rare (16/2572)Hereditary hemorrhagic telangiectasiaGirerd et al [2010]
BMPR1BRare (4/2572)
  • Acromesomelic chrondrodysplasia w/genital anomalies (OMIM 609441)
  • Brachydactyly (OMIM 112600 & 616849)
Chida et al [2012]
BMPR275% of HPAH cases 3
& 201/2572 PAH cases in the US PAH Biobank
Cogan et al [2006]
CAV1Rare (10/2572)
  • Congenital generalized lipodystrophy (OMIM 612526)
  • Type 3 partial lipodystrophy, congenital cataracts, & neurodegeneration syndrome (OMIM 606721)
Austin et al [2012]
ENGRare (6/2572)Hereditary hemorrhagic telangiectasiaGirerd et al [2010]
KCNK3Rare (3/2572)NoneMa et al [2013]
KDRRare (4/2572)NoneSwietlik et al [2020]
SMAD9Rare (13/2572)NoneShintani et al [2009]
TBX4Rare (23/2572)Posterior amelia w/pelvic & pulmonary hypoplasia syndrome (OMIM 601360)Kerstjens-Frederikse et al [2013]
TET2Rare (10/2572)Myelodysplastic syndrome, somatic (OMIM 614286)Potus et al [2020]

Note: HPAH caused by pathogenic variants in the genes listed in Table 1 is inherited in an autosomal dominant manner.

1.

Genes are listed alphabetically.

2.

Out of 2572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group 1 PAH

3.

Since the discovery of BMPR2 [Aström et al 1999], numerous studies consistently show that among families with two or more individuals with confirmed PAH, approximately 75% have a detectable pathogenic germline variant in BMPR2.

4.

Roberts et al [2004] described six individuals with complete type C atrioventricular canal, atrial septal defect, patent ductus arteriosus, partial anomalous pulmonary venous return, and aortopulmonary window with a ventricular septal defect.

5.

In a retrospective study, the records of all persons with a diagnosis of fen-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 & onset of symptoms. Nine (22.5%) of the 40 persons evaluated had a BMPR2 pathogenic variant [Souza et al 2008].

3. Evaluation Strategies to Identify the Genetic Cause of Heritable Pulmonary Arterial Hypertension in a Proband

Establishing a specific genetic cause of heritable pulmonary arterial hypertension (HPAH):

Medical history and physical examination. No particular findings in the medical history or on physical examination distinguish among the various genetic causes of HPAH; however, skeletal anomalies (e.g., patellar irregularities), tracheal and/or bronchial diverticulosis (noted by CT scan or bronchoscopy), developmental delay, and congenital heart disease can be suggestive of TBX4 syndrome [Austin & Elliott 2020].

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) and comprehensive genomic testing (exome sequencing). Gene-targeted testing requires the clinician to hypothesize which genes are likely involved, whereas genomic testing does not.

A multigene panel that includes the genes listed in Table 1 is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

4. Genetic Risk Assessment and Surveillance of At-Risk Relatives

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 and surveillance for at-risk relatives is presented in this section; issues that may be specific to a given family or genetic cause of HPAH 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, or to a Cardiovascular Genetics Center or genetic counselor specializing in cardiac or cardiopulmonary genetics (see NSGC - Find a Genetic Counselor or ABGC Find a Certified Genetic Counselor search tools).

Mode of Inheritance

HPAH is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with HPAH have an affected parent.
  • 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 the proband appears to be the only affected family member (i.e., a simplex case) and has a known HPAH-causing pathogenic variant, molecular genetic testing is recommended for the parents of the proband.
  • If the proband has a known HPAH-associated pathogenic variant that is not identified in either parent, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
  • The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the HPAH-associated 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 a PAH-associated pathogenic variant (and the possibility that gender 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 proband has a known HPAH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a proband with a known PAH-associated pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see Clinical Surveillance for Relatives at Risk).

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 has the pathogenic variant, his or her family members may be at risk.

Clinical Surveillance for Relatives at Risk

Asymptomatic family members of an affected individual in whom the specific genetic cause of HPAH has not been identified. The WSPH, American College of Cardiology, and American Heart Association recommend serial screening by echocardiography of at-risk family members every three to five years to enable early detection and treatment.

Asymptomatic family members of an affected individual who has a known pathogenic variant in an HPAH-associated gene. If a definitive pathogenic variant is identified in the affected individual, molecular genetic testing can be performed in at-risk relatives to clarify their genetic risk:

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.

5. Management of Heritable Pulmonary Arterial Hypertension

See Abman et al [2015] (full text) and Galiè et al [2016] (full text) for evidence-based treatment algorithms for pediatric and adult populations respectively.

Referral centers specializing in diagnosis and therapy of pulmonary arterial hypertension (PAH) are available across the US (see Pulmonary Hypertension Association website). Consultation is encouraged for all persons suspected of having PAH because of the complexity and continuing evolution of diagnosis and treatment.

Unprecedented approval of medications for PAH by the FDA in the last two decades has led to availability of a dozen therapies which all demonstrate some efficacy. However, substantial limitations remain: none of them cures the disease, nor is effective in all patients, nor stops or reverses the underlying pathogenesis (obstruction of the pulmonary arteries).

The most effective among them, continuous IV prostacyclin or prostanoids, delivered by continuous IV or subcutaneous delivery, are the most complicated to administer as they require patient management of a pump for continuous infusion, with a myriad of possible problems, including sepsis related to chronic central venous catheters. Patient preference often dictates the route of medication administration (continuous IV or subcutaneous, aerosol, oral) or side effects determine which agents are personally acceptable.

There are no different therapeutic approaches for pregnant women with PAH; standard PAH-directed care remains a crucial component of care in addition to high-risk obstetric approaches.

Continuous patient monitoring for progression of disease and medication adjustment requires a dedicated multidisciplinary team that communicates seamlessly with multiple specialty pharmacies and insurers.

Chapter Notes

Author Notes

Genetic and genomic discovery efforts in PAH are rapidly progressing. Some sites of interest may 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 patients, 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 patients, families, and related individuals who graciously participate in genetic studies of PAH across the world
  • Lisa Wheeler, former Coordinator of Familial 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

Revision History

  • 23 December 2020 (ha) Comprehensive update posted live; scope changed to overview
  • 11 June 2015 (me) Comprehensive update posted live
  • 20 December 2012 (cd) Revision: pathogenic varaints in ACVRL1, BMPR1B, CAV1, ENG, and SMAD9 found in rare cases to cause FPAH
  • 29 March 2011 (me) Comprehensive update posted live
  • 15 November 2007 (cd) Revision: prenatal diagnosis available
  • 18 July 2007 (me) Comprehensive update posted live
  • 24 March 2006 (jl) Revision: duplication/deletion testing using Southern blot clinically available
  • 29 June 2005 (jl) Revision: sequence analysis clinically available
  • 2 November 2004 (me) Comprehensive update posted live
  • 8 December 2003 (jl) Revision: Summary
  • 18 July 2002 (me) Review posted live
  • 14 January 2002 (jl) Original submission

References

Literature Cited

  • Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99. [PubMed: 26534956]
  • Aström AK, Jin D, Imamura T, Röijer E, Rosenzweig B, Miyazono K, ten Dijke P, Stenman G. Chromosomal localization of three human genes encoding bone morphogenetic protein receptors. Mamm Genome. 1999;10:299–302. [PubMed: 10051328]
  • Austin ED, Elliott CG. TBX4 syndrome: a systemic disease highlighted by pulmonary arterial hypertension in its most severe form. Eur Respir J. 2020;55:2000585. [PubMed: 32409426]
  • Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA 3rd, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–43. [PMC free article: PMC3380156] [PubMed: 22474227]
  • Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376–87. [PubMed: 19837821]
  • Ballard W 3rd, Dixon B, McEvoy CA, Verma AK. Pulmonary arterial hypertension in pregnancy. Cardiol Clin. 2021;39:109–18. [PubMed: 33222807]
  • Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, Robbins IM, Elliott CG. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145:231–6. [PMC free article: PMC3921094] [PubMed: 24135949]
  • Chida A, Shintani M, Nakayama T, Furutani Y, Hayama E, Inai K, Saji T, Nonoyama S, Nakanishi T. Missense mutations of the BMPR1B (ALK6) gene in childhood idiopathic pulmonary arterial hypertension. Circ J. 2012;76:1501–8. [PubMed: 22374147]
  • Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, Stanton KC, Wheeler LA, Phillips JA 3rd, Loyd JE, Nichols WC. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:590–8. [PMC free article: PMC2648061] [PubMed: 16728714]
  • Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmüller P, Fadel E, Sitbon O, Simonneau G, Tregouët DA, Humbert M, Soubrier F. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46:65–9. [PubMed: 24292273]
  • Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119. [PubMed: 26320113]
  • Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jaïs X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, Sitbon O, O'Callaghan DS, Simonneau G, Soubrier F, Humbert M. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010;181:851–61. [PubMed: 20056902]
  • Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, Leter EM, Douwes JM, Van Dijk A, Vonk-Noordegraaf A, Dijk-Bos KK, Hoefsloot LH, Hoendermis ES, Gille JJ, Sikkema-Raddatz B, Hofstra RM, Berger RM. TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension. J Med Genet. 2013;50:500–6. [PMC free article: PMC3717587] [PubMed: 23592887]
  • Kim NH, Delcroix M, Jenkins DP, Channick R, Dartevelle P, Jansa P, Lang I, Madani MM, Ogino H, Pengo V, Mayer E. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013;62:D92–9. [PubMed: 24355646]
  • Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, Shimizu T, Nochioka K, Sato H, Konno R, Satoh K, Miyata S, Shimokawa H. Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. Heart Vessels. 2018;33:939–47. [PMC free article: PMC6060798] [PubMed: 29441403]
  • Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA 3rd, Hamid R, Loyd JE. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:892–6. [PMC free article: PMC3530218] [PubMed: 22923661]
  • Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouët DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass RS, Chung WK. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–61. [PMC free article: PMC3792227] [PubMed: 23883380]
  • McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009a;53:1573–1619. [PubMed: 19389575]
  • McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009b;119:2250–94. [PubMed: 19332472]
  • Morrell NW, Aldred MA, Chung WK, Elliott CG, Nichols WC, Soubrier F, Trembath RC, Loyd JE. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53:1801899. [PMC free article: PMC6351337] [PubMed: 30545973]
  • Potus F, Pauciulo MW, Cook EK, Zhu N, Hsieh A, Welch CL, Shen Y, Tian L, Lima P, Mewburn J, D'Arsigny CL, Lutz KA, Coleman AW, Damico R, Snetsinger B, Martin AY, Hassoun PM, Nichols WC, Chung WK, Rauh MJ, Archer SL. Novel mutations and decreased expression of the epigenetic regulator TET2 in pulmonary arterial hypertension. Circulation. 2020;141:1986–2000. [PMC free article: PMC7299806] [PubMed: 32192357]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J. 2004;24:371–4. [PubMed: 15358693]
  • Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet. 2009;46:331–7. [PubMed: 19211612]
  • Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. [PMC free article: PMC6351336] [PubMed: 30545968]
  • Souza R, Humbert M, Sztrymf B, Jaïs X, Yaïci A, Le Pavec J, Parent F, Hervé P, Soubrier F, Sitbon O, Simonneau G. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J. 2008;31:343–8. [PubMed: 17959632]
  • Swietlik EM, Greene D, Zhu N, Megy K, Cogliano M, Rajaram S, Pandya D, Tilly T, Lutz KA, Welch CCL, Pauciulo MW, Southgate L, Martin JM, Treacy CM, Penkett CJ, Stephens JC, Bogaard HJ, Church C, Coghlan G, Coleman AW, Condliffe R, Eichstaedt CA, Eyries M, Gall H, Ghio S, Girerd B, Grünig E, Holden S, Howard L, Humbert M, Kiely DG, Kovacs G, Lordan J, Machado RD, Mackenzie Ross RV, McCabe C, Moledina S, Montani D, Olschewski H, Pepke-Zaba J, Price L, Rhodes CJ, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Vonk Noordegraaf A, Wharton J, Wild JM, Wort SJ, Lawrie A, Wilkins MR, Trembath RC, Shen Y, Chung WK, Swift AJ, Nichols WC, Morrell NW, Gräf S. Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension. Circ Genom Precis Med. 2020. 2020;14:e003155. [PMC free article: PMC7892262] [PubMed: 33320693]
  • Zhu N, Pauciulo MW, Welch CL, Lutz KA, Coleman AW, Gonzaga-Jauregui C, Wang J, Grimes JM, Martin LJ, He H, Shen Y, Chung WK, Nichols WC, et al. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019;11:69. [PMC free article: PMC6857288] [PubMed: 31727138]
Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2021 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1485PMID: 20301658

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...