Primary pulmonary hypertension 1

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: BMPR2 (HGNC:1078)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 09/11/2017
• Curation Status: Released - Under Revision (1.2.4)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
BMPR2	pulmonary hypertension, primary, 1 (0024533)	178600	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion of moderate according to the rubric. There are ongoing surveillance trials to gather effectiveness that may impact the assertion in the future. Re-evaluation should be considered.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Deterioration of pulmonary and cardiac function / Annual echocardiogram	2	2C	1B	3	8CB
Deterioration of pulmonary and cardiac function / Pharmacotherapy	2	2C	1A	3	8CA
Deterioration of pulmonary and cardiac function / Avoidance of exacerbating exposures	2	2C	0C	3	7CC

Severity of Outcome

Prevalence of the Genetic Condition

Estimates of the prevalence of pulmonary arterial hypertension (PAH) range from 15 to 60 cases per million adult population. Estimate of PAH incidence range from 2.4 to 10 cases per million adult population per year. These statistics include individuals with idiopathic, heritable, and drug induced PAH. PAH is inherited in less than 10% of cases. Pathogenic variants in BMPR2 are the most common genetic cause of familial PAH.

Clinical Features (Signs / symptoms)

PAH, a subset of pulmonary hypertension (PH), is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries leading to the resistance to blood flow through the lungs. As a result, the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow, which eventually progresses to heart failure and premature death. Right heart catheterization with a mean pulmonary artery pressure of 25mm Hg or more with a pulmonary artery wedge pressure of 15mm Hg or less is needed to confirm the diagnosis of PAH. The symptoms of PH are non-specific and mainly related to progressive right ventricular dysfunction. Initial symptoms are typically induced by exertion and may include: shortness of breath, fatigue, weakness, angina, and syncope. Less commonly patients may also describe dry cough and exercise-induced nausea and vomiting. Symptoms at rest occur only in advanced cases. Individuals with PAH are classified into four functional categories by the World Health Organization (WHO FC): class I: no limitation of physical activity, class II: slight limitation of physical activity, class III: marked limitation of physical activity, class IV: inability to care out physical activity without symptoms.

Natural History (Important subgroups & survival / recovery)

All ages are affected, but the mean age at diagnosis of PAH has been reported as ranging from 36 to 65 years. Because the symptoms of PAH are nonspecific and develop slowly diagnosis is often delayed for months or even years. It is currently not possible to predict those who will ultimately develop PAH, although women are at increased risk compared to men. Females are twice as likely to be affected as males; however, survival is worse in males than females. Studies suggest that the female predisposition to PAH may be directly related to the effects of the metabolites of estrogen. Before the availability of disease-specific therapy in the mid-1980’s, the median life expectancy at the time of diagnosis was 2.8 years. Current therapy improves clinical function, but has a modest effect on survival.PAH associated with a pathogenic variant in BMPR2 occurs at an earlier age and is associated with more severe and rapidly progressive disease. Data from an individual patient meta-analysis (N=1,550 patients with PAH; 29% with an identified BMPR2 pathogenic variant) found that at diagnosis, individuals with a BMPR2 pathogenic variant were younger (mean age 35.4 years vs. 42 years; p<0.0001) and had a higher mean pulmonary artery pressure and pulmonary vascular resistance, and a lower cardiac index. During a median of 5.4 years of follow up, individuals with a BMPR2 pathogenic variant were more likely to reach the composite outcome of death or lung transplantation (HR: 1.42 (95% CI: 1.15-1.75; p=0.0011) with similar results among men and women.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Heterozygous BMPR2 pathogenic variants account for approximately 75% of familial PAH and up to 40% of apparently sporadic cases. Hereditary transmission has been reported in approximately 6 to 10% of patients with PAH. Pathogenic variants in BMPR2 have been identified in 50-90% of these individuals.

Tier 3

To date, more than 200 families with heritable PAH are known in the US, including 120 families in whom the specific BMPR2 pathogenic variant is known.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

BMPR2 pathogenic variants have a penetrance of 20-30%.

Tier 3

The lifetime risk of PAH for males with a BMPR2 pathogenic variant is 14%, for females the risk is 42%.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information related to relative risk was identified.

Expressivity

For those patients who develop PAH the variability in survival across patients is broad, ranging from sudden death to decades (rare).

Tier 4

Intervention Effectiveness

Patient Management

Individuals at risk for PAH should undergo aggressive treatment for any existing conditions that contribute to the development or worsening of PH (e.g., sleep apnea and systemic hypertension).

Tier 2

Surveillance

Even in the absence of symptoms, individuals known to be at risk for the development of PAH based on the presence of a known pathogenic variant in BMPR2 should undergo monitoring for the development of PAH. The appropriate interval and type of screening has not been established. Recommendations for screening vary from annual echocardiography to ongoing clinical monitoring for the development of symptoms that would signal disease progression and warrant initiation of pharmacotherapy. There is an ongoing longitudinal study that should clarify issues such as optimal screening strategies and predictors of progression to PAH in asymptomatic BMPR2 carriers (NCT01600898).

Tier 2

No approved therapy for PAH has been shown to prevent progression of the underlying pulmonary vascular disease. PAH remains an incurable disease; currently, with clinicians attempt to manage it with pharmacotherapy. The prognosis of PAH is significantly worse in patients with advanced disease, PAH therapies delay clinical worsening and data are accumulating suggesting that early treatment improves long-term outcome.

Tier 3

A systematic review of 37 studies involving 4,192 patients that assess the effectiveness of drug treatment for adults with diagnosed PAH found inconclusive evidence regarding mortality reduction. The reviewers note that few deaths were observed in these studies due to their limited duration, leading to wide confidence intervals and lack of statistical power to detect a difference in mortality; however, a consistent direction of effect and demonstrated improvements in other outcomes, including functional and hemodynamic measures, support that a mortality reduction might exist. Increases in 6-minute walk distance (6MWD) ranging from 27.9 meters (95% CI, 10.3 to 45.4) to 39.9 meters (CI, 21.4 to 58.4) were observed in trials of all drug classes when compared with placebo or standard therapy. The reported minimal clinically meaningful difference in 6MWD is 33 meters for individuals with PAH.

Tier 1

Circumstances to Avoid

Individuals who are at risk for PAH should avoid appetite-suppressant medications as these have been associated with an increased risk of PH.

Tier 3

Cocaine, amphetamines, and related compounds causing vasoconstriction, have been anecdotally associated with PH.

Tier 4

Other medications that have anecdotal suggestion of increased risk of PH, including estrogen compounds used as oral contraceptives or hormone replacement therapy. Anecdotal reports associating pregnancy with onset of PH raise some concern about the risks involved with pregnancy; however, there is no published consensus regarding the best approach to birth control in women with PAH. Because avoidance of exogenous systemic estrogen is desirable, many experts prefer intrauterine devices (IUDs).

Tier 3

The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and PH in susceptible individuals.

Tier 4

Nature of Intervention

Nature of Intervention

The initial screening for PAH may include cardiac imaging including echocardiography. Other universal management may include the avoidance of factors that may increase the likelihood of PAH. For those with signs of PH, right heart catheterization is used for diagnosis. For the minority of patients diagnosed with PAH, treatment can be varied and may eventually progress to supportive care, symptomatic treatment, disease-specific agents, and potentially lung transplantation.

Context: Adult

Chance to Escape Clinical Detection

Because the symptoms of heritable PAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some patients report no symptoms, and diagnosis is suspected on an incidental basis because of cardiac findings such as murmur, then supported by echocardiogram. Diagnosis is often delayed for months or even years, in part because heritable PAH is uncommon and thus rarely considered. The time to diagnosis from onset of symptoms may be shorter in familial PAH, perhaps because of heightened familial awareness.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			BMPR2			178600	0024533	0008347, 0001999

References List

ED Austin, JE Loyd, JA Phillips. Heritable Pulmonary Arterial Hypertension. (2002) [Updated Jun 11 2015]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1485/

Evans JD, Girerd B, Montani D, Wang XJ, Galie N, Austin ED, Elliott G, Asano K, Grunig E, Yan Y, Jing ZC, Manes A, Palazzini M, Wheeler LA, Nakayama I, Satoh T, Eichstaedt C, Hinderhofer K, Wolf M, Rosenzweig EB, Chung WK, Soubrier F, Simonneau G, Sitbon O, Graf S, Kaptoge S, Di Angelantonio E, Humbert M, Morrell NW. (2016) BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. The Lancet. Respiratory medicine. 4(2):129-37.

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McCrory DC, Coeytaux RR, Schmit KM, Kraft B, Kosinski AS, Mingo AM, Vann LM, Gilstrap DL, Hargett CW, Lugogo NL, Heidenfelder BL, Posey R, Irvine RJ, Wing L, Pendergast K, Dolor RJ. (2013) . Pulmonary Arterial Hypertension: Screening, Management, and Treatment.

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. (2009) 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. Journal of the American College of Cardiology. 53(17):1573-619.

Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, Palevsky HI, Rich S, Sood N, Rosenzweig EB, Trow TK, Yung R, Elliott CG, Badesch DB. (2014) Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 146(2):449-475.