Contributors to and consequences of burnout among clinical genetic counselors in the United States.

Prior research has found that many genetic counselors (GCs) experience burnout. Studies of other clinicians have demonstrated that burnout can have significant detrimental consequences for clinicians, patients, and the healthcare system. We sought to explore the prevalence of, contributors to, and consequences of burnout among GCs. We performed a secondary data analysis of baseline data from Me-GC, a randomized controlled trial of meditation for GCs. We applied a systems model of burnout proposed by the National Academy of Medicine (NAM), which depicts burnout arising from a combination of contributors that include both work system and individual mediating factors, and then leading to consequences. Validated self-report scales were used to measure burnout and most contributors and consequences. Female and white GCs were over-represented in our sample. Over half (57.2%) of the 397 participants had Professional Fulfillment Index scores indicative of burnout. Multiple potential contributors were associated with burnout, consistent with its known multifactorial nature. Among work system factors, higher levels of burnout were associated with insufficient administrative support, lack of autonomy, and not feeling valued by non-GC colleagues. Individual mediating factors associated with greater burnout included higher levels of anxiety, depression, and stress. Participants with lower levels of burnout reported greater mindfulness, resilience, and use of professional self-care behaviors. Among variables categorized as consequences, higher levels of burnout were associated with lower levels of empathy, counseling alliance, and positive unconditional regard, as well as higher reactive distress, and a greater desire to reduce the amount of time spent on clinical care. Given the prevalence and potential consequences of burnout observed here, it is imperative that the field take steps to mitigate burnout risk.

U.S. Genetic counselors' perceptions of inpatient genetic counseling: A valuable model for medically complex patients.

Some genetic counselors (GCs) provide care in the inpatient setting. However, there is little literature on inpatient genetic counseling. The purpose of our study was to describe GC's experiences with the provision of genetic counseling services within inpatient care settings. Participants were recruited from respondents to a quantitative survey study on inpatient genetic counseling, which recruited GCs via the National Society of Genetic Counselors forum. GCs seeing at least five inpatients per year were invited to participate in semi-structured interviews. The interview guide explored how and why their inpatient genetic counseling service started, workflow, and the perceived impact of the service. Interviews were transcribed, inductive analysis was used to develop a codebook, and thematic analysis was used to identify themes. Twenty-one inpatient genetic counselors participated in the study. Many participants worked primarily in outpatient roles with some inpatient duties (61.9%), while the rest worked primarily in inpatient roles (38.1%). Most participants have provided inpatient care for <2 years (66.7%). Many participants were involved in inpatient care across multiple specialties (66.7%), most frequently, pediatrics, neonatology, and neurology. Three themes were identified: (a) The convenience of inpatient genetic counseling leads to increased access to appropriate genetics care for medically complex patients and their inpatient healthcare providers, (b) the inpatient genetic counseling process and workflow is not standard and has multiple moving parts, and (c) genetic counselors are fulfilled by the diverse and unique opportunities of the inpatient care setting despite the emotional intensity of this environment. Participants described their inpatient care as valuable because it increases access to genetics services and adds genetics expertise to multidisciplinary inpatient teams. Overall, participants perceive inpatient genetic counseling as a way to bring genetics care directly to patients at a critical time point in their care, which benefits medically complex patients and their multidisciplinary inpatient team.

Genetic counselor experiences with telehealth before and after COVID-19.

While genetic counselor (GC) utilization of telehealth has increased in recent years, the onset of the COVID-19 pandemic significantly accelerated the adoption of telehealth for many. We investigated GC experiences with telehealth including perceived advantages, disadvantages, and barriers using a one-time online survey of GCs who provided direct patient care in recent years. The survey examined experiences with telehealth before and after the onset of COVID-19. We made broad comparisons to findings from a similar study our research team conducted five years ago. GCs reported an increase in the utilization of telehealth over time, with significant increases from pre-2017 (44%) to pre-COVID-19 (70%) and then to present (87%) (p<.001 and .02, respectively). There was no significant change in the total number of hours worked from pre-COVID-19 to the time of survey completion, nor were there significant changes in the amount of time spent on clinical responsibilities or interfacing with patients. However, the total number of hours worked in telehealth significantly increased (z = 5.05, p<.001) as did the percent of time spent interacting with patients via telehealth [t(72)=3.74, p<.001, d = 0.44]. Participants overwhelmingly preferred video (84%) over telephone; this differs from our previous survey where video was the preferred modality for 59% (p<.001). We utilized open-ended questions to elicit reasons for modality preference. The most-cited barrier to telehealth utilization was billing/reimbursement issues, with 39% noting this obstacle. This is consistent with our previous study where 30% cited billing/reimbursement as the primary barrier. These findings indicate a need for continued efforts to improve billing and reimbursement for genetic counseling offered via telehealth. They also present an opportunity for additional exploration regarding patient preferences for telehealth modality.

Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Background: A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers. Methods: Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints. Results: Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years. Conclusions: The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.

Multidimensional structure-function relationships in human ß-cardiac myosin from population-scale genetic variation.

Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human ß-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within ß-cardiac myosin. We first developed computational models of the human ß-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.

Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience.

PurposeTo describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories.MethodsRetrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar.ResultsOf 688 laboratory classifications, 124 (18%) differed from the clinicians' classifications. Most differences in classification would probably affect clinical care of the patient and/or family (83%, 103/124). The frequency of discordant classifications differed depending on the testing laboratory (P < 0.0001) and the testing laboratory's classification (P < 0.00001). For the majority (82/124, 66%) of discordant classifications, clinicians were more conservative (less likely to classify a variant pathogenic or likely pathogenic). The clinicians' classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing laboratory's classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, P = 0.0002).ConclusionThe clinical team disagreed with the laboratory's classification at a rate similar to that of reported disagreements between laboratories. Most of this discordance was clinically significant, with clinicians tending to be more conservative than laboratories in their classifications.

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations.

Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

Mindfulness Among Genetic Counselors Is Associated with Increased Empathy and Work Engagement and Decreased Burnout and Compassion Fatigue.

Genetic counselors experience high rates of compassion fatigue and an elevated risk for burnout, both of which can negatively impact patient care and retention in the profession. In other healthcare professions, mindfulness training has been successfully used to address similar negative psychological sequelae and to bolster empathy, which is the foundation of our counseling work. We aimed to assess associations between mindfulness and key professional variables, including burnout, compassion fatigue, work engagement, and empathy. Data were collected via an anonymous, online survey that included validated measures of mindfulness and these key professional variables. The survey was completed by 441 genetic counselors involved in direct patient care. Half of the respondents (50.1%) reported engaging in yoga, meditation, and/or breathing exercises. Mindfulness was positively correlated with work engagement (r = 0.24, p < 0.001) and empathy (as measured through four subscales: perspective taking (r = 0.15, p = 0.002), empathic concern (r = 0.11, p = 0.03), fantasy (r = - 0.11, p = 0.03) and personal distress (r = - 0.15, p = 0.001)). Mindfulness was negatively correlated with compassion fatigue (r = - 0.48, p < 0.001) and burnout (r = - 0.50, p < 0.001). Given these findings, mindfulness training may be a valuable addition to graduate and continuing education for genetic counselors. The integration of mindfulness into the genetic counseling field will likely improve professional morale and well-being, while promoting workforce retention and bolstering the relational and counseling aspects of our clinical work.

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification.

We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.

Theories for Psychotherapeutic Genetic Counseling: Fuzzy Trace Theory and Cognitive Behavior Theory.

Psychotherapeutic genetic counseling is an increasingly relevant practice description. In this paper we aim to demonstrate how psychotherapeutic genetic counseling can be achieved by using psychological theories to guide one's approach to working with clients. We describe two illustrative examples, fuzzy trace theory and cognitive behavior theory, and apply them to two challenging cases. The theories were partially derived from evidence of beneficial client outcomes using a psychotherapeutic approach to patient care in other settings. We aim to demonstrate how these two specific theories can inform psychotherapeutic genetic counseling practice, and use them as examples of how to take a psychological theory and effectively apply it to genetic counseling.

Response to A Different Vantage Point Commentary: Psychotherapeutic Genetic Counseling, Is it?

Whether genetic counseling is a form of psychotherapy is open for debate. Early practicioners in genetic counseling described it as such, and this claim has been replicated in recent publications. This commentary is a rebuttal to the claim that genetic counseling is distinct from psychotherapty. We argue that it is a a form of psychoterapy that aims to help clients manage a health threat that affects their psychological wellbeing, paralleling the goals of psychotherapy.

Sports genetics moving forward: lessons learned from medical research.

Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.

Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

Clinical interpretation and implications of whole-genome sequencing.

IMPORTANCE: Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES: To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS: An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES: Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS: Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE: In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

QTc prolongation and family history of sudden death in a patient with desmin cardiomyopathy.

This case report describes a pregnant female patient who presented with new-onset congestive heart failure symptoms and prolonged QTc, with strong family history of sudden death. Endomyocardial biopsy and genetic testing revealed myocardial desmin accumulation and a previously described mutation in the DES (desmin) gene, as well as variants in two LQT genes, SCN5A and KCNH2. The case highlights the phenotypic variability for a particular desmin genotype, and the possible interaction of desminopathy with LQT variants not independently associated with large differences in current properties or QT prolongation from wild type.

Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.

BACKGROUND: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2. METHODS: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used co-immunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres. RESULTS: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 (alpha-actinin 1) and GJA1 (gap junction protein alpha 1), 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing. CONCLUSIONS: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

Invasive prenatal testing decisions in pregnancy after infertility.

OBJECTIVE: This study assessed decisional conflict about invasive prenatal testing among women pregnant after infertility. METHODS: We surveyed 180 pregnant women with a history of infertility using a mixed methods cross-sectional design. Difficulty in deciding whether to have prenatal testing was measured using the Decisional Conflict Scale. RESULTS: A minority of women (31%) chose to have invasive prenatal testing. Most participants (72%) reported low decisional conflict (score < 25; mean = 22.1; standard deviation = 23.2; range: 0-100). Half (53%) of the participants said that infertility made the testing decision easier. Qualitative data suggest that infertility makes the decision easier by clarifying relevant values and priorities. Most infertility characteristics studied were not significantly associated with decisional conflict. Variables associated with higher decisional conflict included infertility distress due to rejection of a childfree lifestyle, disagreement with others about testing, and choosing to have invasive testing after having had treatment for infertility. CONCLUSIONS: For some women, infertility may make the invasive prenatal testing decision easier. Women with the greatest need for decisional support were those who have had treatment and choose invasive testing, who disagree with others about their testing choice, or who are particularly distressed about being childless.

Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy.

Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.