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Cardiovascular genetic counseling has expanded as an established genetic counseling specialty over the last 20 years. Despite guidelines recommending genetic counseling for heritable cardiac diseases, there have been limited descriptions of the practice model types used for different clinical indications seen in this genetic counseling subspecialty. We aimed to describe current clinical practice models used by cardiovascular genetic counselors and to document practice model strengths, challenges, and areas for improvement. Genetic counselor respondents (n = 63) who self-reported seeing cardiovascular indications were recruited through the National Society of Genetic Counselors and Twitter. They completed a survey describing the types of healthcare professionals with whom they collaborate to see common cardiovascular indications, the nature of their collaboration, and their qualitative experiences with their practice models. Clinical indications addressed in this survey were hypertrophic cardiomyopathy, dilated cardiomyopathy, all other cardiomyopathies, arrhythmias, aortopathies, dyslipidemias, pulmonary arterial hypertension, and congenital heart defects. Data were analyzed using descriptive statistics and thematic analysis. We found that the composition of multidisciplinary provider practice models varies by indication, though general cardiologists were the most common collaborative provider reported. Practice models including geneticists were most common for aortopathy indications. Overall, the majority of respondents were satisfied with the practice models they reported. While a wide variety of successes, challenges, and areas for improvement of practice models were reported, collaboration, communication, and access to appropriate providers for patient care were consistent themes across these three questions. To our knowledge, this is the first description of practice models used by cardiovascular genetic counselors. The results of this study add to the knowledge of this specialty of genetic counseling and assist in understanding the needs and challenges for developing cardiovascular genetics programs and clinics., (© 2022 National Society of Genetic Counselors.)

For the past two decades, the guidelines put forth by the American College of Medical Genetics and Genomics (ACMG) detailing providers' clinical responsibility to recontact patients have remained mostly unchanged, despite evolving variant interpretation practices which have yielded substantial rates of reclassification and amended reports. In fact, there is little information regarding genetic counselors' roles in informing patients of reclassified variants, or the process by which these amended reports are currently being handled. In this study, we developed a survey to measure current experiences with amended variant reports and preferences for ideal management, which was completed by 96 genetic counselors from the United States and Canada. All respondents indicated they were the individuals responsible for disclosing initial positive genetic testing results and any clinically actionable reclassified variant reports, and over half (56%) received at least a few amended variant reports each year. Nearly a quarter (20/87) of respondents reported having a standard operating procedure (SOP) for managing amended reports and all were very satisfied (12/20) or satisfied (8/20) with the SOP. Of those without a protocol, 76% (51/67) would prefer to have an SOP implemented. Respondents reported a preference for (1) laboratories to send amended variant reports directly to the genetic counselor or ordering physician through email or an online portal, and (2) notification to patients ideally occurring through a phone call. In the event that the original genetic counselor is inaccessible, respondents reported a preference for reports to be sent directly to another genetic counselor (36%) on the team or the clinic in general (27%). Information from this study provides insight into the current practices of genetic counselors as applied to amended reports and what improvements may increase the efficiency of the reporting process. Moreover, these results suggest a need for an updated statement addressing duty to recontact, specifically as it applies to amended variant reports., (© 2021 National Society of Genetic Counselors.)

Congenital heart defects (CHDs) occur in 8 of 1000 live-born children, making them common birth defects in the adolescent population. CHDs may have single gene, chromosomal, or multifactorial causes. Despite evidence that patients with CHD want information on heritability and genetics, no studies have investigated the interest or knowledge base in the adolescent population. This information is necessary as patients in adolescence take greater ownership of their health care and discuss reproductive risks with their physicians. The objectives of this survey-based study were to determine adolescents' recall of their own heart condition, to assess patient and parent perception of the genetic contribution to the adolescent's CHD, and to obtain information about the preferred method(s) for education. The results show that adolescent patients had good recall of their type of CHD. Less than half of adolescents and parents believed their CHD had a genetic basis or was heritable; however, adolescents with a positive family history of CHD were more likely to believe that their condition was genetic (p = 0.0005). The majority of patients were interested in receiving additional genetics education and preferred education in-person and in consultation with both parents and a physician. The adolescents who felt most competent to have discussions with their doctors regarding potential causes of their heart defect previously had a school science course which covered topics in genetics. These results provide insight into adolescents' perceptions and understanding about their CHD and genetic risk and may inform the creation and provision of additional genetic education.

Cardiovascular genetic counseling (CVGC) is recommended for a variety of inherited heart conditions; however, its impact on patient empowerment has not been assessed. The Genetic Counseling Outcome Scale (GCOS) is a validated patient reported outcome tool which measures empowerment to capture the impact of clinical genetics services. As a routine clinical practice at our center, adult patients attending a CVGC appointment complete the 24-item GCOS survey and a 5-item survey on knowledge of cardiac surveillance recommendations for relatives prior to the clinic visit. To investigate the effect of CVGC, we contacted participants after the appointment to repeat these surveys prior to genetic test result disclosure. Forty-two participants completed pre- and post-GC surveys. The mean difference between pre- and post-GC empowerment scores was 17.5 points (mean pre-GC score = 118.5, mean post-GC score = 136, p < 0.0001; effect size, d = 0.94). Forty percent of individuals (17/42) were aware of surveillance recommendations for at-risk family members prior to GC; this increased to 76% of individuals (32/42) post-GC (p < 0.01). This is the first study to explore patient empowerment before and after GC in a cardiology setting. The results demonstrate a significant increase in empowerment and awareness of recommendations for at-risk relatives as a result of CVGC. This study demonstrates the utility of CVGC in patient care., (© 2019 National Society of Genetic Counselors.)

RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study.

There are minimal data on the impact of genetic counselors in subspecialty clinics, including the pediatric arrhythmia clinic. This study aimed to describe the clinical encounters of a genetic counselor integrated into a pediatric arrhythmia clinic. In the 20 months between July 2015 and February 2017, a total of 1914 scheduled patients were screened for indications relevant for assessment by a genetic counselor. Of these, the genetic counselor completed 276 patient encounters, seeing 14.4% of all patients in clinic. The most expected and common indications for genetic counselor involvement were related to suspicion for primary heritable arrhythmia conditions, though patients seen in this clinic display a wide range of cardiac problems and many additional indications for genetic evaluation were identified. Roughly 75% (211/276) of encounters were for personal history of confirmed/suspected heritable disease, including cardiac channelopathies, cardiomyopathies, ventricular arrhythmias, and congenital heart defects, and 25% (65/276) were for family history of disease, including long QT syndrome and sudden unexplained death. Overall, this study shows that about 1 in 7 patients seen in a pediatric arrhythmia clinic have indications that likely benefit from genetic counselor involvement and care. Similar service delivery models embedding genetic counselors in pediatric arrhythmia clinics should be encouraged, and this model could be emulated to increase patient access to genetic counseling services.

In the last decade, an increasing number of cardiac conditions have been shown to have a genetic basis. Cardiovascular genetic counseling has emerged as a subspecialty aiming to identify unaffected at-risk individuals. An important sector of this at-risk population also includes expectant mothers, in whom unique clinical challenges may arise. Genetic counselors, especially those in cardiovascular and prenatal settings, have an opportunity to identify and assist women who may benefit from cardiovascular care during pregnancy. This paper provides basic management and genetic evaluation principles for affected women, as well as guidance on identifying those who are at risk. We provide considerations for cardiac surveillance in pregnancy and the post-partum period. Finally, key psychosocial issues that appraise how to best provide support to at risk women as they make informed decisions are discussed. We propose that a team approach including cardiology, maternal fetal medicine, and genetic counseling best serves this patient population. Ongoing questions addressing an evidence based approach to cardiovascular genetic conditions in pregnancy still remain. Thus, well-designed research protocols are essential to mark progress in this area.

The development of high-throughput technologies such as next-generation sequencing (NGS) has allowed for thousands of DNA loci to be interrogated simultaneously in a fast and economical method for the detection of clinically deleterious variants. Whenever a clinical diagnosis is known, a targeted NGS approach involving the use of disease-specific gene panels can be employed. This approach is often valuable as it allows for a more specific and clinically relevant interpretation of results. Here, we describe the customization, validation, and utilization of a commercially available targeted enrichment platform for the scalability of clinical diagnostic cardiovascular genetic tests, including the design of the gene panels, the technical parameters for the quality assurance and quality control, the customization of the bioinformatics pipeline, and the post-bioinformatics analysis procedures. Regions of poor base coverage were detected and targeted by Sanger sequencing as needed. All panels were successfully validated using genotype-known DNA samples either commercially available or from research subjects previously tested in outside clinical laboratories. In our experience, utilizing several of the sub-panels in a clinical setting with 33 real-life cardiovascular patients, we found that 20% of tests requested were reported to have at least one pathogenic or likely pathogenic variant that could explain the patient phenotype. For each of these patients, the positive results may aid the clinical team and the patients in best developing a disease management plan and in identifying relatives at risk.

We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Inherited cardiovascular (CV) conditions are common, and comprehensive care of affected families often involves genetic testing. When the clinical presentations of these conditions overlap, genetic testing may clarify diagnoses, etiologies, and treatments in symptomatic individuals and facilitate the identification of asymptomatic, at-risk relatives, allowing for often life-saving preventative care. Although some professional society guidelines on inherited cardiac conditions include genetic testing recommendations, they quickly become outdated owing to the rapid expansion and use of such testing. Currently, these guidelines primarily discuss the benefits of targeted genetic testing for identifying at-risk relatives. Although most insurance policies acknowledge the benefit and the necessity of this testing, many exclude coverage for testing altogether or are vague about coverage for testing in probands, which is imperative if clinicians are to have the best chance of accurately identifying pathogenic variant(s) in a family. In response to uncertainties about coverage, many commercial CV genetic testing laboratories have shouldered the burden of working directly with commercial payers and protecting patients/institutions from out-of-pocket costs. As a result, many clinicians are unaware that payer coverage policies may not match professional recommendations for CV genetic testing. This conundrum has left patients, clinicians, payers, and laboratories at an impasse when determining the best path forward for meaningful and sustainable testing. Herein, we discuss the need for all involved parties to recognize their common goals in this process, which should motivate collaboration in changing existing frameworks and creating more sustainable access to genetic information for families with inherited CV conditions.

Sudden cardiac death due to heritable ventricular arrhythmias is an important cause of mortality, especially in young healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family-based risk assessment and information. In addition, disease-specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Sudden cardiac death (SCD) is a leading cause of mortality worldwide. Although coronary artery disease remains the most common substrate for SCD, primary cardiac genetic diseases, presenting with or without structural heart abnormalities, play a significant role. In the last 30 years, the study of large family pedigrees allowed the discovery of causative genes unveiling the genetic basis of diseases such as primary cardiomyopathies and arrhythmia syndromes, which are known to increase the risk of SCD. However, recent technological advancement with the ability to perform massive parallel sequencing and analyze the entire genome has uncovered a higher level of complexity in the genetic predisposition for cardiac diseases, which are usually characterized by Mendelian inheritance patterns. Clinical genetic testing, historically shaped around a monogenic Mendelian disorder paradigm, is now facing the challenge to adopt and adapt to a more complex model in which a significant portion of subjects may present with multi-allelic inheritance involving additional genes that could modulate the severity and type of disease-related phenotypes. Here, we will try to provide a viewpoint that will hopefully foster further debate in the field., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field., Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice., Conclusions: Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology., (© 2015 American Heart Association, Inc.)

Haploinsufficiency of CHD7 (OMIM# 608892) is known to cause CHARGE syndrome (OMIM# 214800). Molecular testing supports a definitive diagnosis in approximately 65-70% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays., (© 2013 Wiley Periodicals, Inc.)