Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Group 1 pulmonary arterial hypertension (PAH) refers to a set of rare proliferative vascular diseases that result in a marked increase in pulmonary arterial pressure and resistance due to narrowing of the pulmonary arterioles.¹  Vasoconstriction, fibrosis, cell proliferation, and thrombosis contribute to these pathological processes.²  In some cases, PAH may be associated with risk factors such as drug or toxin exposure (eg anorexigens) or other diseases (such as connective tissue disease, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis). When no underlying cause is found, PAH is labeled “idiopathic PAH” (IPAH). There has been increasing recognition that genetic factors play a role in the development of familial and sporadic IPAH.

Heritable PAH (HPAH) is a subgroup of PAH that includes cases with more than one affected family member (familial PAH [FPAH]) and/or cases with an established causative genetic variant, regardless of family history (ie, apparently sporadic IPAH found to have predisposing germline variant on genetic testing). The definition of HPAH also applies to genetically mediated pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD-PCH), which are pathologically distinct forms of PAH with hemodynamic similarities. In addition, some individuals with PAH presumed associated with anorexigen use³  or congenital heart disease⁴  have also been shown to have an underlying genetic cause.

While multiple single-gene causes and candidate genes for HPAH have been discovered (Tables 1 and 2), the BMPR2 gene remains the most common and well-studied cause of HPAH. At least 10% to 40% of IPAH and 70% to 80% of FPAH have been shown to have an underlying pathogenic variant¹⁰  and a proportion of PVOD-PCH has been shown to be caused by biallelic pathogenic variants in the EIF2AK4 gene.^11,12  Inclusion of newly discovered PAH genes increases genetic test yield in FPAH to 92% to 95% (B.G., unpublished data, October 2021).

HPAH is predominately inherited in an autosomal-dominant pattern conferring a 50% risk for first-degree relatives to inherit the familial susceptibility variant. Most HPAH genes exhibit incomplete penetrance and variable expressivity, with the exception of EIF2AK4-mediated PVOD-PCH, which is completely penetrant and inherited in an autosomal-recessive pattern.

The purpose of this article is to offer a perspective on the current utility of genetic counseling and testing for PAH; to provide a framework for appropriate anticipatory guidance, supportive counseling, and incorporation of genetic test results into patient care; and to identify areas for future genetics research.

Genetic counseling refers to professional guidance and support provided to patients and their relatives who seek to learn about the inherited nature of a disease, the recurrence risk in family members, and the availability of proactive measures such as clinical surveillance and/or genetic testing for an identified familial variant, when applicable. A key aspect of genetic counseling is also the interpretation and incorporation of genetic test results into clinical care. Genetic counseling is provided by trained specialists such as a geneticist or a genetic counselor and is regarded as a valuable and essential medical service by clients and providers.^13–15 

Several professional societies recommend genetic counseling with genetic testing (Table 3) for individuals with HPAH or IPAH, familial or sporadic PVOD-PCH, and for first-degree relatives once a familial susceptibility variant has been identified,^16–21  as well as for individuals with congenital heart disease–associated PAH,²⁰  anorexiant PAH,^18,21  and hereditary hemorrhagic telangiectasia–related PAH.²¹ 

Genetic counseling occurs in two steps, pretest and posttest (Table 4; Figure 1). Genetic counseling prior to undergoing genetic testing is essential to guide the patient or at-risk relative in making an informed decision about testing, and provides valuable disease-specific education and resources that are beneficial to the patient and their family members, even if genetic testing is not pursued.

Pretest genetic counseling begins with collection and assessment of the affected individual’s medical and family history which can allow for the diagnosis of unrecognized familial disease, assessment of inheritance pattern, and identification of at-risk relatives in the family, as well as influence the choice of tests if a particular gene is suspected to be involved. Education surrounding PAH symptoms, inheritance, and the genetic testing process, including cost and insurance coverage, as well as benefits, limitations, and potential psychosocial risks of genetic testing, are addressed to allow thoughtful decision-making around testing. Ideally, genetic testing starts with an affected individual as explained in Table 4.

Posttest genetic counseling involves communication with the patient regarding the test result, its interpretation, recommendations for the patient if applicable, and recommendations for relatives based on the result and family history. Posttest genetic counseling also involves provision of resources including a family letter to assist in informing at-risk relatives regarding their potential risk for PAH and recommendations for additional evaluation.

Due to genetic heterogeneity and an inability to distinguish the underlying genetic cause based on personal and family history in most instances, a comprehensive PAH gene panel including all genes with clear association to PAH is generally recommended and is similar in cost to performing single-gene analysis. If involvement of one gene is strongly suspected, single-gene testing with reflex to the panel in case of a negative result may be considered. Whole exome or whole genome sequencing are generally not needed for sporadic adult-onset IPAH as they have similar yield as a panel test but are more expensive. Whole exome or whole genome sequencing may be considered in large HPAH families with a negative result on panel testing, or in pediatric PAH due to the higher likelihood of novel gene discovery in these populations, and the involvement of genes that are not typically associated with PAH.⁴ 

Unlike many medical tests, the results of genetic testing for most disorders, including PAH, provide a probabilistic result rather than a binary genetic/not genetic outcome. Panel-based testing identifies multiple genetic variants, and these must be carefully interpreted by the testing laboratory to categorize each variant as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign based on the strength of evidence for or against pathogenicity.²²  While there may be ample evidence available to categorize some variants, other variants may lack evidence to classify as disease-causing or benign, and are placed in the uncertain category. As genetic testing of PAH patients becomes more routine, new evidence is likely to result in reclassification of variants. The results are therefore complex, and best handled by professionals with in-depth genetics knowledge.

Identification of a pathogenic or likely pathogenic variant in a PAH-associated gene is considered a positive result. Pinpointing a genetic variant causative of PAH establishes the diagnosis of HPAH in individuals previously diagnosed with IPAH or associated PAH, and confirms genetic etiology in those with FPAH. On occasion, the involvement of a specific gene could have medical management implications for the affected individual. For example, identification of biallelic EIF2AK4 mutations establishes a diagnosis of PVOD-PCH without a lung biopsy, as well as guides treatment, as vasodilators are contraindicated⁸  while early referral for lung transplantation is indicated.^8,19  Identification of TBX4-mediated disease in a case of resolved persistent pulmonary hypertension of the newborn (PPHN) would indicate a need for annual surveil-lance with echocardiogram due to the risk of recurrence.⁶  Importantly, knowing the familial susceptibility variant allows for cascade genetic testing (ie, targeted testing for the familial variant in at-risk relatives). Cascade genetic testing even in young children is considered necessary due to the availability of effective medical interventions.

Family members harboring an FPAH-susceptibility variant have an increased risk of developing PAH and other features associated with the identified gene. They can also pass the variant to their offspring. Genetically mediated PAH and PVOD-PCH can manifest as early as infancy,^8,23  and therefore, clinical screening with echocardiograms is initiated in childhood,²⁰  and repeated every 1 to 3 years or sooner if symptoms develop to facilitate early detection and treatment of PAH.^17,20  In the recently published outcomes from the DELPHI-2 study,²⁴  in which 55 adult asymptomatic BMPR2 mutation carriers received annual multimodal screening for a minimum of 2 years, the overall incidence of PAH was 2.3% per year. Individuals were diagnosed with PAH at an earlier stage than is typical in the absence of proactive clinical screening. Additionally, the 5 patients who were diagnosed with PAH via screening were started on oral combination therapy and at the end of 6 years, they remained in a low mortality-risk category.²⁴ 

If the FPAH-susceptibility variant is known, prenatal diagnosis and preimplantation genetic testing become available family planning options for affected and at-risk asymptomatic males who wish to ensure biological offspring have not inherited predisposition to PAH.^25,26  Pregnancy in affected or unaffected at-risk females is discouraged as it can be life-threatening. It is also unclear if preimplantation genetic testing with gestational surrogacy is safe, as the effect of ovarian stimulation in females with a PAH-susceptibility variant remains unknown.

Guideline authors recommend that adult at-risk individuals in a family receive genetic counseling so they can make an informed decision about undergoing genetic testing and/or serial clinical screening for PAH.^17,19,21  It is also common practice for at-risk relatives choosing not to undergo family-variant testing to have serial clinical screening.

Family members who test negative for the FPAH-susceptibility variant have the general population risk of about 1 in a million to develop PAH, and their children are not at risk for inheriting the familial variant.

The absence of a PAH susceptibility variant on a comprehensive PAH panel test in the affected individual is considered a genotype-negative result. In the case of FPAH, a negative genetic test result in the proband is clearly uninformative, does not rule out monogenic etiology, and indicates there are a proportion of genes or genetic mechanisms responsible for FPAH that are as-yet undiscovered. Professional societies recommend clinical surveillance for asymptomatic first-degree relatives with serial echocardiograms even when the affected relative is genotype-negative,^16,17,20  and screening is ideally repeated annually.¹⁸  In the case of sporadic IPAH, a negative genetic test is reassuring, but does not rule out a genetic etiology. Clinical screening for first-degree relatives in this context is not indicated,²⁵  but the proband is encouraged to inform close relatives regarding the diagnosis and symptoms so they can seek an evaluation if cardiorespiratory symptoms arise.²⁰ 

In most cases, identification of one or more variants of uncertain significance is treated like an uninformative negative result with respect to cascade clinical surveillance, that is, clinical surveillance is recommended for at-risk relatives in FPAH families while surveillance is not recommended for family members of patients with IPAH. In the case of a novel or suspicious variant of uncertain significance identified in a family with HPAH, segregation studies may be performed to understand its role in PAH susceptibility.

Retesting affected individuals with a negative result when new PAH genes are identified should also be considered.

Due to the utility of genetic counseling and testing in identifying family members at-risk for PAH, guidelines recommending these services for PAH have been available for over 15 years. Yet, it appears that these recommendations are not often followed by medical providers in the United States, largely owing to a lack of knowledge surrounding PAH genetics, and perceived lack of relevance of genetic counseling and testing in clinical care.²⁷  Other reasons for not utilizing genetic services highlighted in the same study²⁷  included high cost or insurance noncoverage for genetic services and a lack of access to genetic counselors.

Additionally, a 2020 survey of patients with IPAH conducted by the United Kingdom Pulmonary Hypertension Association highlighted preference of a majority (74%) of patients with IPAH to undergo genetic testing, and their desire to have cascade genetic testing offered to relatives if the specific genetic cause was pinpointed (80%).²⁸  Further, PAH is typically advanced by the time it is diagnosed, but with studies starting to document improved outcomes with available therapy even in severe PAH,^24,29,30  it is imperative to implement proactive measures (ie genetic testing with serial evaluation) in individuals at risk for HPAH, to detect disease at an early stage when the impact of therapy can be maximized. Genetic testing has become extremely affordable in the last 5 years. Postnatal targeted testing for a familial variant is in the range of US$200 with many insurance companies covering genetic counseling as well as genetic testing. Therefore, the time has arrived for better utilization of genetics services for patients with PAH. It may be easier to obtain insurance coverage for recommended serial screening in the presence of a PAH susceptibility variant. Genetic counselors specialized in cardiovascular disease or general genetics are ideally suited to coordinate genetics-related care. Providers without local access to a genetic counselor can request services through telegenetics companies.

Despite recent advances in gene discovery for HPAH, there remains a proportion of gene-elusive FPAH cases. Further, in families with a known predisposition, utility of predictive testing is still complicated by incomplete penetrance of disease. Studies to discover the missing genetic contributors to HPAH, as well as to understand contributors to reduced penetrance and variable expressivity are needed. In addition, the most effective clinical screening protocol for individuals at high risk of HPAH addressing at which age evaluations should be initiated, which screening modalities should be utilized, and what the frequency of screening should be in genotype positive versus negative families is yet to be established.