Optimizing efficiency and skill utilization: Analysis of genetic counselors' attitudes regarding delegation in a clinical setting.

This study assessed genetic counselors' (GCs) perceptions of delegation as a tool to increase workforce efficiency and help meet the current gap between the number of genetic service providers and the number of patients. GCs were recruited to participate via an online survey that assessed activities (categorized as typical genetic counseling, administrative, or professional development) performed by a clinical genetic counselor. Respondents indicated which activities represent their largest time consumers, their willingness to delegate these activities, and barriers to and perceived outcomes of delegation. Overall, respondents indicated that they spend 25% of their time performing administrative activities that they would largely be willing to delegate; however, respondents were generally unwilling to delegate many typical genetic counseling and professional development activities, citing concerns regarding accuracy and liability, and highlighting the belief that these activities constitute the core role of a genetic counselor. Respondents indicated that delegation of time-consuming administrative activities would increase access to genetic services and improve job satisfaction. Additionally, differences were identified among clinical specialties regarding which activities were selected as top time consumers, indicating that potential targets of re-allocation of time or delegation may be variable. This research indicates a need to reduce the number of administrative tasks in which GCs are directly involved to re-allocate time toward core responsibilities, direct patient care, and professional development, the result of which is more efficient use of the GC skill-set.

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2 Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.

Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies.

CONTEXT.­: Immunohistochemical expression of mismatch repair (MMR) protein is a well-accepted method for routine screening for Lynch syndrome with relatively high sensitivity and specificity. Occasionally, however, immunohistochemistry (IHC) can yield an equivocal result with poor reproducibility and the potential for misdiagnosis. OBJECTIVE.­: To determine the frequency and significance of indeterminate MMR IHC expression in patients routinely screened for Lynch syndrome and correlation with germline mutation studies. DESIGN.­: Semiquantitative scoring of MMR IHC was performed by image analysis in 479 cases, of which 380 were colorectal and 99 endometrial cancer. Scores of 10% or more, less than 10%, and 0% were used as cutoffs for retained, indeterminate, and loss of expression, respectively. Negative and indeterminate IHC results were confirmed by mutational studies. RESULTS.­: Four hundred eighteen of 479 cases (87.2%) were reported as retained expression, 45 (9.3%) as loss of expression, and 16 (3.3%) as indeterminate expression. Fifteen of 45 (33.3%) and 8 of 16 (50%) with loss and indeterminate expression, respectively, were found to have Lynch syndrome by germline studies. The overall frequency of Lynch syndrome in our patient population was 4.8% (23 of 479), and 34.7% of these (8 of 23) were associated with indeterminate IHC expression. In the indeterminate group, MLH1 germline mutation was the most frequent (6 of 13; 46.2%), followed by MSH6 (4 of 13; 30.7%). CONCLUSIONS.­: Our findings provide further evidence that indeterminate IHC should be further investigated for possible MMR germline mutation. Guidelines for interpretation of MMR IHC and the establishment of more objective criteria for defining indeterminate results are important to improve the sensitivity and specificity of the IHC assay.

Public prescription drug plan coverage for antiretrovirals and the potential cost to people living with HIV in Canada: a descriptive study.

BACKGROUND: Antiretrovirals are expensive and people living with HIV may experience a range of financial burdens when accessing these medications. Our aim was to describe the policy of all Canadian public drug insurance programs for antiretroviral drugs and illustrated how these policies might affect patients' annual out-of-pocket expenditures. METHODS: In December 2017, we reviewed public drug programs offering antiretroviral coverage in Canada using government websites to summarize eligibility criteria. We estimated the annual out-of-pocket costs incurred by people living with HIV by applying the cost-sharing rules to 2 hypothetical cases, a single man and a married woman with a net household income of $39 000 and $80 000, respectively, receiving identical prescriptions in different jurisdictions. RESULTS: We observed substantial variation in the subsidy provided based mainly on geography, income and age. All 5 federal programs and 6 of 13 provincial and territorial jurisdictions offered universal coverage. In the remaining regions, patients spend up to several thousand dollars annually depending on income (Manitoba), age and income (Ontario, Saskatchewan) and age, income and drug costs (Quebec and Newfoundland and Labrador). We found the greatest variation for our higher income case, with out-of-pocket expenses ranging from 0 to over 50% of the antiretroviral cost. INTERPRETATION: There is considerable inter- and intra-jurisdiction heterogeneity in the cost-sharing policies for antiretrovirals across Canada's public drug programs. Policy reforms that either eliminate or set national standards for copayments, deductibles or premiums would minimize variation and could reduce the risk of cost-associated non-adherence to HIV therapy.

To stay or to go? Postretirement housing choices of single Baby Boomer women.

Single women of the Baby Boomer generation are often financially disadvantaged in the retirement planning process due to their lower accumulated savings compared to male retirees. This disadvantage impacts significant consumption decisions such as postretirement housing choices. This study uses the theory of planned behavior to examine how certainty in intentions influences preparing and planning for postretirement housing. A typology of single Baby Boomer women is developed based on their financial, demographic, and psychological circumstances. Each segment likely requires different informational strategies and financial services to foster proactive planning for retirement. Significant implications exist for social policy and the financial services sector.

Genetic Counseling Assistants: an Integral Piece of the Evolving Genetic Counseling Service Delivery Model.

This study explores the potential impact of the genetic counseling assistant (GCA) position on the efficiency of the genetic counseling field, evaluates attitudes regarding expansion of the genetic counseling field to include the GCA, and presents data on GCA endeavors and GCA job tasks as reported by GCAs, certified genetic counselors (CGCs), and program directors (PDs). Data on GCA roles and attitudes toward different aspects of the GCA position were collected via surveys of CGCs who have worked with GCAs, PDs who have and have not had experience with GCAs in their programs, and GCAs. We analyzed responses from 63 individuals: 27 PDs, 22 CGCs, and 14 GCAs. GCAs' impact on efficiency was calculated via internal analysis of genetic patient volume per genetic counselor within the University of Texas Southwestern (UTSW) patient database prior to, and since the addition of, a GCA to the practice. The response rates for PDs, CGCs, and GCAs were 27 %, 79 %, and 61 %, respectively. Every CGC stated the GCA increased their efficiency. CGCs with a GCA reported a 60 % average increase in patient volume. This figure was congruent with internal data from the UTSW cancer genetics program (58.5 % increase). Appropriate responsibilities for GCAs as reported by CGCs and PDs (>90 %) include: data entry, shipping tests, administrative tasks, research, and ordering supplies. Regarding GCAs delivering test results, there was response variation whether this should be a job duty: 42 % of CGCs agreed to GCAs delivering negative results to patients, compared to 22 % of program directors. Twenty-two percent of PDs expressed concern about the job title "Genetic Counseling Assistant." Ninety percent of CGCs felt that GCA was a career path to becoming a CGC, compared to 42 % of PDs. Eighty-three percent of GCAs who decided to apply to CGC graduate programs were accepted. We conclude the addition of a GCA to a genetic counseling practice contributes to increased efficiency and is one way to expand the reach of the profession.

Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis.

Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis.

High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration.

INTRODUCTION: Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. RESULTS: We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence. CONCLUSIONS: Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes.

Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic.

Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.

Prediction of Cancer Prevention: From Mammogram Screening to Identification of BRCA1/2 Mutation Carriers in Underserved Populations.

BACKGROUND: The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence. METHODS: We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers. FINDINGS: We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention. INTERPRETATION: Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.

Proactive case finding to improve concurrently curative and palliative care in patients with end-stage liver disease.

BACKGROUND: Palliative care and preparation for liver transplantation are often perceived as conflicting for patients with end-stage liver disease (ESLD). We sought to improve both simultaneously through a case finding and care coordination quality improvement intervention. METHODS: We identified patients with cirrhosis using validated ICD-9 codes and screened them for ESLD by assessing medical records at a VA hospital for either a model for end-stage liver disease (MELD) ≥14 or a diagnosis of hepatocellular carcinoma (HCC) between October 2012 and January 2013. A care coordinator followed veterans from the index hospitalization through April 2013 and encouraged treating physicians to submit liver transplant evaluation consults for all veterans with a MELD ≥14 and palliative care consults for all veterans with a MELD ≥20 or inoperable HCC. RESULTS: We compared rates of consultation for 49 hospitalized veterans and compared their outcomes to 61 pre-intervention veterans. Veterans were more likely to be considered for liver transplantation (77.6% versus 31.1%, p<0.001) and receive palliative care consultation during the intervention period, although the latter finding did not reach statistical significance (62.5% versus 47.1%, p=0.38). CONCLUSIONS: Active case finding improved consideration for liver transplantation without decreasing palliative care consultation.

An internal performance assessment of CancerGene Connect: an electronic tool to streamline, measure and improve the genetic counseling process.

CancerGene Connect (CGC) is a web-based program that combines the collection of family and medical history, cancer risk assessment, psychosocial assessment, report templates, a result tracking system, and a patient follow up system. The performance of CGC was assessed in several ways: pre-appointment completion data analyzed for demographic and health variables; a time study to assess overall time per case and to compare the data entry by the genetic counselor compared to the patient, and a measured quality assessment of the program via observation and interview of patients. Prior to their appointment, 52.3% of 2,414 patients completed the online patient questionnaire section of CGC. There were significant differences in completion rates among racial and ethnic groups. County hospital patients were less likely to complete the questionnaire than insured patients (p < 0.0001); and likewise uninsured patients and patients with Medicare/Medicaid were less likely to complete the questionnaire than private patients (p < 0.0001). The average genetic counseling time per case was 82 min, with no significant differences whether the counselor or the patient completed CGC. CGC reduces genetic counselor time by approximately 14-46% compared to average time per case using traditional risk assessment and documentation methods previously reported. All surveyed users felt the questionnaire was easy to understand. CGC is an effective tool that streamlines workflow, and provides a standardized data collection tool that can be used to evaluate and improve the genetic counseling process.

State of inertia: psychological preparation of single Australian and UK baby boomer women for retirement housing change.

The transition into retirement is an important life phase that presents significant challenges in respect to well-being, lifestyle, and consumption choices. This article examines the consumption context of housing after retirement, in particular for the low-resourced cohort of single baby boomer women. Utilizing an extended Theory of Planned Behavior model, we examine the relationship between intention and actual behavior, in this case financial advice seeking, as an important component of the psychological preparedness of single female baby boomer women. Our analysis showed both Australian and UK single baby boomer women display different behaviors in terms of seeking advice and their mental preparedness to adjust to a change in their living arrangements. The findings are discussed in terms of their implications for policy and further research.

Resistance to noise-induced hearing loss in 129S6 and MOLF mice: identification of independent, overlapping, and interacting chromosomal regions.

Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 × CBACa) and (MOLF × CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17.

Engagement with Care, Substance Use, and Adherence to Therapy in HIV/AIDS.

Engagement with care for those living with HIV is aimed at establishing a strong relationship between patients and their health care provider and is often associated with greater adherence to therapy and treatment (Flickinger, Saha, Moore, and Beach, 2013). Substance use behaviors are linked with lower rates of engagement with care and medication adherence (Horvath, Carrico, Simoni, Boyer, Amico, and Petroli, 2013). This study is a secondary data analysis using a cross-sectional design from a larger randomized controlled trial (n = 775) that investigated the efficacy of a self-care symptom management manual for participants living with HIV. Participants were recruited from countries of Africa and the US. This study provides evidence that substance use is linked with lower self-reported engagement with care and adherence to therapy. Data on substance use and engagement are presented. Clinical implications of the study address the importance of utilizing health care system and policy factors to improve engagement with care.

Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations.

INTRODUCTION: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance. METHODS: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals). RESULTS: T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06). CONCLUSION: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

BMP pathway regulation of and by macrophages.

Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC) treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.

The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience.

PURPOSE: The advent of next-generation sequencing for cancer susceptibility genes holds promise for clinical genetics application, but the practical issues surrounding integration of this testing into the clinical setting have not been well addressed. This article describes the clinical experience of genetic counselors in an academic and community setting with next-generation sequencing cancer panels. METHODS: Between April 2012 and January 2013, 60 next-generation sequencing panels were ordered. A retrospective review was conducted to determine the indication for ordering the results of the tests and the patient management based on the results. RESULTS: Ten tests were canceled due to out-of-pocket costs or previously identified mutations. Among the 50 tests, 5 (10%) showed a positive result. Moreover, 15 of the 50 (30%) panels detected variant(s) of uncertain significance or variant(s) suspected benign. CONCLUSION: We propose clinical guidelines for identifying high-risk patients who should be offered this testing. Our data support the National Comprehensive Cancer Network recommendations that next-generation sequencing be ordered as a second-tier test for high-risk individuals with cancer by trained cancer genetics providers. Literature review and expert knowledge should be used to create management plans for the identification of both positive and variants of uncertain significance results. Providers should be aware of limitations regarding reimbursement for testing and recommended management strategies.

Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension.

Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.