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

PH Professional Network: Genetic Counseling and Pulmonary Arterial Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.

Our understanding of pulmonary hypertension (PH) has advanced steadily. Almost 100 years ago, light microscopy provided the earliest insights into a rare progressive and fatal disease, primary pulmonary hypertension (“PPH”). Pathologists described the histopathology of PPH, with terms like “plexogenic” and “microthromboembolic” PPH. Pathologists, who specialized in pulmonary vascular disease, identified two rare disorders, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), that mimicked PPH clinically, but were distinctly different under the microscope.By the middle of the 20th century, the introduction of pulmonary artery catheterization to the study of cardiovascular diseases produced a new level of understanding of PH based upon physiologic observations of intravascular pressures and flows, with an emphasis on mechanisms that caused constriction and relaxation of pulmonary arterioles. This era supported early efforts to treat sporadic PPH and familial PPH, now known as idiopathic and heritable pulmonary arterial hypertension (PAH) with vasodilators, eventually leading to treatments which targeted three pathways integral to vasoconstriction and vasodilation of pulmonary arterioles.Even as pathologic, physiologic, and treatment studies proceeded during the second half of the 20th century, the genetic era began. Investigators took advantage of scientific advances in genetics to discover heritable causes of PH. The first breakthrough occurred in 2000, when two research teams independently reported that mutations in the gene (BMPR2), encoding the bone morphogenetic protein type 2 receptor, caused familial PPH. Over the next two decades investigators linked DNA sequence variations in 16 additional genes to heritable forms of PAH, including PVOD and PCH. These discoveries shaped a new understanding of PAH.Investigators quickly determined that BMPR2 regulated the proliferation of vascular cells, not vasoconstriction. Recognition of the pivotal role of cellular proliferation and transforming growth factor β (TGF-β) signaling paved the way for a new approach to the treatment of PAH. In the Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PULSAR), sotatercept, a fusion protein that impairs activation of a TGFβ pro-proliferative pathway, produced a greater reduction in pulmonary vascular resistance than placebo. Now studies are underway to assess the efficacy and safety of sotatercept across a broad spectrum of PAH disease severity.We have entered a new era of understanding and treating PAH, as genetics moves to center stage. This issue of Advances in Pulmonary Hypertension was organized to serve as a valuable resource for the PH community. The first article, authored by Drs. Carrie Welch and Wendy Chung of Columbia University, provides a comprehensive overview of the genomics of pulmonary hypertension. With this foundation in place, the second article, authored by Rachel Sullivan, MD (Stanford University) and Eric Austin, MD (Vanderbilt University) reviews the relationships between specific gene sequence variations and PAH phenotypes that clinicians are likely to encounter.In recent years genetic counseling and genetic testing have become important affordable services for patients with PAH and their families. Sumathi Rachamadugu, MSc, MS and Melanie Emmerson, MS (Intermountain Healthcare) collaborated with Barbara Girerd, PhD (Université Paris-Saclay) and Hunter Best, PhD (University of Utah) to provide an in depth introduction pretest genetic counseling, genetic testing, and posttest genetic counseling for PAH patients and their families. The PH Professional network contribution by Athena Angelopoulos, MS and Rachel Farrell, MS (University of California San Francisco) complements the preceding article by providing additional details related to genetic counseling and testing for PAH patients and their families.Finally, Drs. Austin, Chung, and Yu, joined us for a roundtable discussion on the genetics of pulmonary hypertension. Participants shared their personal knowledge of the history of genetic research and discovery related to PH, their advice on discussing genetic aspects of PH with patients and families, their thoughts about involving genetic counselors and ordering genetic tests, as well as how genetic test results influence treatment decisions and how knowledge of molecular pathways informs the development of new medications to treat PAH.In closing, we thank the authors and everyone at PHA and Allen Press who worked so hard to produce this issue of Advances.

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Key role of the molecular autopsy in sudden unexpected death

Evidence-based guidelines recommend cascade genetic counseling and testing for hereditary cancer syndromes, providing relatives the opportunity for early detection and prevention of cancer. The current standard is for patients to contact and encourage relatives (patient-mediated contact) to undergo counseling and testing. Direct relative contact by the medical team or testing laboratory has shown promise but is complicated by privacy laws and lack of infrastructure. We sought to compare outcomes associated with patient-mediated and direct relative contact for hereditary cancer cascade genetic counseling and testing in the first meta-analysis on this topic. We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade testing. Eligible trials were subjected to meta-analysis. Eighty-seven studies met inclusion criteria. Among relatives included in the meta-analysis, 48% (95% CI, 38 to 58) underwent cascade genetic counseling and 41% (95% CI, 34 to 48) cascade genetic testing. Compared with the patient-mediated approach, direct relative contact resulted in significantly higher uptake of genetic counseling for all relatives (63% [95% CI, 49 to 75] v 35% [95% CI, 24 to 48]) and genetic testing for first-degree relatives (62% [95% CI, 49 to 73] v 40% [95% CI, 32 to 48]). Methods of direct contact included telephone calls, letters, and e-mails; respective rates of genetic testing completion were 61% (95% CI, 51 to 70), 48% (95% CI, 37 to 59), and 48% (95% CI, 45 to 50). Most relatives at risk for hereditary cancer do not undergo cascade genetic counseling and testing, forgoing potentially life-saving medical interventions. Compared with patient-mediated contact, direct relative contact increased rates of cascade genetic counseling and testing, arguing for a shift in the care delivery paradigm, to be confirmed by randomized controlled trials.

Disparities in completion of genetic testing and counseling for Lynch syndrome in high-risk patients diagnosed with endometrial cancer (601)

40-Year-Old Woman With Breathlessness and Fatigue

Although infants with persistent pulmonary hypertension of the newborn (PPHN) experience some relief and therapeutic benefit from current therapies, over 50% have a limited or transient response and significant morbidity. There is no consistency in the best first line treatment throughout hospitals in the United States. Ventilation with high levels of oxygen or inhaled nitric oxide (NO) are typical strategies for improving the extracorporeal membrane oxygen, although they remain unproven to increase survival rates. While oxygen may stimulate endothelial nitric oxide synthase (eNOS) and NO production dilating the pulmonary vasculature, it also fuels the production of reactive oxygen species (ROS). ROS is likely to have counterproductive effects; in addition to stimulating vascular smooth muscle cell proliferation and increasing vascular tone, ROS may directly regulate eNOS and NO. The recent article by Farrow and colleagues (3) in AJP-Lung investigates the role of ROS on eNOS. By using recombinant human superoxide dismutase (rhSOD), they observed 1) increased eNOS activity and expression, 2) increased tetrahydrobiopterin (BH4), a cofactor critical to the function of eNOS, and 3 )a decrease in oxidative stress, in addition to the stimulation of NO production and ultimately pulmonary vasodilatation. The observations they made may be paramount to increasing the survival of infants with PPHN and may lead to an adapted treatment regimen that addresses the pitfalls of current therapeutic approaches. PPHN When the pulmonary circulation fails to respond to natural stimuli, including increased oxygen tension, ventilation, and shear stress, it does not undergo the shift from the high resistance state in utero to a postnatal low resistance system, enabling efficient pulmonary gas exchange and oxygenation. Impaired NO-cGMP signaling has been shown to be critical to the regulation of pulmonary circulation in the newborn, and clinical strategies have involved administration of inhaled NO since the early 1990s (6, 10). While effective in immediate relief due to vasodilatation, the infants can enter an inhaled NO dependency state, and thus inhaled NO proffers poor long-term relief. The necessity for extensive research into the regulation of perinatal circulation and the changes that occur upon ventilation have led to improved and more specific therapeutic approaches for infants with PPHN over the past 30 years. Despite this, PPHN is still associated with significant shortterm and long-term morbidity. Farrow et al. (3) strive to dissect the signaling pathways, determining the impact of ROS and elucidating the potential of decreasing oxidative stress as a therapeutic approach in PPHN. This study is published in a milieu of recent publications exploring the functional abnor

Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required

Genetic counseling is “the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.” Traditionally, this process includes collecting and interpreting the family and medical history, risk assessment, a comprehensive educational process for potential genetic testing, informed consent, and psychosocial assessment and support (National Society of Genetic Counselors' Definition Task Force et al. 2006). While genetic counseling falls within the scope of many health care professionals, clinical geneticists (physicians) and masters level genetic counselors have been working in the United States for more than 40 years, providing genetic counseling primarily for single-gene conditions. Debate about what “genomic counseling” will include and who will practice it has been fueled by the transition from single-gene focused genetic counseling and testing to a full genomic medicine approach. The routine incorporation of genomic medicine will likely induce differences in the scope, approach and process of genetic counseling (Table ​(Table1).1). In this commentary, I will discuss the several areas where practice will likely change as we move toward “genomic” counseling, with a focus on the unique skills and roles that genetic counselors and clinical geneticists provide. Table 1 Changes that will impact the transition to “genomic counseling.”

Background: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes’ discovery. Results: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Discussion: Our study revealed elevated plasma levels of inflammatory mediators in different PAH subgroups and CTEPH at baseline and at 1-year follow-up, whereby CXCL9 and IL-8 may prove to be prognostic markers for CTEPH patients. While this study is exploratory and hypothesis generating, our data indicate an important role for IL-8 and CXCL9 in CHD and CTEPH patients considering the increased plasma levels and the observed correlation with survival. Conclusion: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

M6 - Presymptomatic Genetic Counseling In Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: A Potential Model For Genetic Testing In Neurodegenerative Disorders