Assessing and attending to psychosocial concerns in genetic counseling: Proposing the BATHE method.

The process of identifying and responding to patients' social, emotional, and psychological concerns is a required skill for training and practicing genetic counselors. Patients' health outcomes are improved when genetic counselors attend to these "psychosocial" concerns. Still, the process of eliciting, assessing, and attending to patients' psychosocial concerns in the genetic counseling setting is not well defined in the literature nor is it performed consistently.

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

Multisite Validation of a Functional Assay to Adjudicate Brugada Syndrome-Associated Variants.

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants is challenging, and ≈79% of missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.

Inequities in atrial fibrillation trials: An analysis of participant race, ethnicity, and sex over time.

Background: Despite the importance of racial and ethnic representation in clinical trials, limited data exist about the enrollment trends of these groups in atrial fibrillation (AF) trials over time.

Objective: The purpose of this study was to examine the characteristics of contemporary AF clinical trials and to evaluate their association with race and ethnicity over time.

Methods: We performed a systematic search of all completed AF trials registered in ClinicalTrials.

Generation of two familial hypercholesterolemia patient-specific induced pluripotent stem cell lines harboring heterozygous mutations in the LDLR gene.

Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.

Analysis of financial barriers experienced by prospective genetic counseling students.

Purpose: High costs of applying to genetic counseling graduate programs (GCGPs) are likely a barrier to workforce diversification. We sought to determine application costs and assess differences between individuals of historically underrepresented racial and ethnic backgrounds in medicine (hURM) and non-hURM applicants.

Methods: Applicants to GCGPs between 2005 to 2020 were surveyed about application history, related expenses, volunteer hours, and financial resources; 383 responses were analyzed.

Minimum information and guidelines for reporting a multiplexed assay of variant effect.

Multiplexed assays of variant effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines have led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.

Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.

Rare structural variants (SVs) - insertions, deletions, and complex rearrangements - can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore long-read genomes of 68 individuals from the Undiagnosed Disease Network (UDN) with no previously identified diagnostic mutations from short-read sequencing. Using our optimized SV detection pipelines and 571 control long-read genomes, we detected 716 long-read rare (MAF < 0.

Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels.

APOE codes for apolipoprotein E (ApoE), which plays an important role in lipid and lipoprotein metabolism and homeostasis of tissue lipid content. Several variants in APOE have been associated with inherited dyslipidemias, and a subsequent increased risk of developing premature coronary artery disease (CAD). However, these variants and their impact on risk can be thought of on a spectrum, with some being more monogenic in nature, and others contributing in a polygenic/multifactorial manner.

Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.

Background: To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents.

Methods: We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar.

Characteristics of contemporary atrial fibrillation clinical trials and their association with industry sponsorship.

Background: Industry sponsorship is an important source of funding for atrial fibrillation (AF) clinical trials, the implications of which have not been analyzed.

Objective: The purpose of this study was to determine the characteristics of contemporary AF clinical trials and to evaluate their association with funding source.

Methods: We systematically assessed all completed AF trials registered in the ClinicalTrials.

Knowledge and attitudes on implementing cardiovascular pharmacogenomic testing.

Pharmacogenomics has the potential to inform drug dosing and selection, reduce adverse events, and improve medication efficacy; however, provider knowledge of pharmacogenomic testing varies across provider types and specialties. Given that many actionable pharmacogenomic genes are implicated in cardiovascular medication response variability, this study aimed to evaluate cardiology providers' knowledge and attitudes on implementing clinical pharmacogenomic testing. Sixty-one providers responded to an online survey, including pharmacists (46%), physicians (31%), genetic counselors (15%), and nurses (8%).

Multi-site validation of a functional assay to adjudicate Brugada Syndrome-associated variants.

Brugada Syndrome (BrS) is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in the cardiac sodium channel gene, . Interpreting the pathogenicity of missense variants is challenging and ~79% of missense variants in ClinVar are currently classified as Variants of Uncertain Significance (VUS). An -BrS automated patch clamp assay was generated for high-throughput functional studies of Na1.

Neuromuscular and cardiovascular phenotypes in paediatric titinopathies: a multisite retrospective study.

Background: Pathogenic variants in cause a spectrum of autosomal dominant and recessive cardiovascular, skeletal muscle and cardioskeletal disease with symptom onset across the lifespan. The aim of this study was to characterise the genotypes and phenotypes in a cohort of +paediatric patients.

Methods: Retrospective chart review was performed at four academic medical centres.

Genetic counselors and congenital heart disease: Clinical roles, genetic testing practices, and perceived genetic testing utility.

Genetic counseling and genetic testing are essential for individuals with congenital heart disease/defects (CHD/CHDs). However, the clinical practices of genetic counselors (GCs) and their preferences for different CHD genetic testing strategies are previously unexplored. To address these gaps, GCs (n = 112) representing diverse specialties completed an online survey regarding their counseling and testing practices for syndromic CHD and apparently isolated/non-syndromic CHDs (iCHD).

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

Background And Aims: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants.

Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3.

Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants.