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What is this plain language summary about? This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. What were the results? 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. - After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. - Researchers saw some improvement in KCCQ scores. - Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study ( NCT02057341 ) Phase 2 long-term extension study ( NCT02351856 ) Phase 3 REALM-DCM study ( NCT03439514 )

The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported.Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes.Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99).Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.

BackgroundAs availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.MethodsWe analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.ResultsFor 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.ConclusionsAccess to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Background: Lamin A/C gene ( LMNA )-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA -related dilated cardiomyopathy. Methods: Patients with LMNA -related dilated cardiomyopathy in New York Heart Association class II–IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. Results: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. Conclusions: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA -related dilated cardiomyopathy. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02057341.

Lamin A/C gene (Patients withTwelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.ARRY-371797 was well tolerated and resulted in increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients withURL: https://clinicaltrials.gov; Unique identifier: NCT02057341.

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is ~20x over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of the MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical and functional characteristics of MFN2 Q400 versus wild-type and representative CMT2A-causing MFN2 mutants. All MFN2 mutants we studied suppressed mitochondrial fusion, the canonical MFN2 function. Compared to CMT2A mutants MFN2 R94Q and T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 Q400 had normal GTPase activity with impaired conformational shifting. GTPase-defective MFN2 mutants, but not MFN2 Q400, suppressed mitochondrial motility, provoked mitochondrial depolarization and reduced mitochondrial respiration. By contrast, MFN2 Q400 was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouseMfn2gene induced perinatal cardiomyopathy with no other organ involvement. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cardiomyoblasts expressing MFN2 Q400 exhibited multiple mitophagy defects, but normal mitochondrial respiration. MFN2 Q400 is the first known natural mitophagy- and shape change-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for its enrichment in clinical cardiomyopathy.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.

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Background: Assuring that relatives are informed about a genetic diagnosis and have appropriate medical follow-up can be challenging. We hypothesize that communal coping (CC)—an approach in which a group views a stressor (such as a new genetic diagnosis) as our problem, versus my or your problem, and takes joint action to address it—can help families to address this challenge. A better understanding of CC could also inform counseling interventions to promote CC and family follow-up. Methods: In the Dilated Cardiomyopathy (DCM) PM study (Precision Medicine), living first-degree relatives of DCM probands were invited to undergo clinical screening; 31% of these did so. This research program offers the opportunity to determine the frequency of CC in DCM families, assess whether CC attitudes and actions occurred more commonly among families in which family members participated, and conduct prospective follow-up to evaluate family coping and counseling needs over time. Results: The proposed studies will provide evidence about the frequency of CC attitudes and actions among DCM families, assess the association of CC with increased family follow-up, and identify counseling needs related to family follow-up. Conclusions: The DCM PM study offers an opportunity to test the hypothesis that CC contributes to increased family follow-up and generate evidence to inform counseling interventions to encourage such follow-up.

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.

Dilated cardiomyopathy (DCM) is a cardiovascular disease of genetic aetiology that causes substantial morbidity and mortality, and presents considerable opportunity for disease mitigation and prevention in those at risk. Foundational to the process of caring for patients diagnosed with DCM is a clinical genetic evaluation, which always begins with a comprehensive family history and clinical evaluation. Genetic testing of the proband, the first patient identified in a family with DCM, within the context of genetic counselling is always indicated, regardless of whether the DCM is familial or non-familial. Clinical screening of at-risk family members is also indicated, as is cascade genetic testing for actionable variants found at genetic testing in the proband. Clinicians now have expansive panels with many genes available for DCM genetic testing, and the approaches used to evaluate rare variants to decide which are disease-causing continues to rapidly evolve. Despite these recent advances, only a minority of cases yield actionable variants, even in familial DCM where a genetic aetiology is highly likely. This underscores that our knowledge of DCM clinical genetics remains incomplete, including variant interpretation and DCM genetic architecture. Emerging data suggest that the single-variant Mendelian disease model is insufficient to explain some DCM cases, and rather that multiple variants, both common and rare, and at times key environmental factors, interact to cause DCM. A simple model illustrating the intersection of DCM genetic architecture with environmental impact is provided.

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self‐administered surveys examining direct‐to‐participant enrollment and web‐based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web‐based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1‐hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM.

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.Methods and results: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment-emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.Conclusions: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre-clinical findings of direct activation of LA contractility.

Background: Coronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology. Methods: The DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial. Results: Of 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with Conclusions: Of 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.The presence of DCM in a proband.Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.ClinicalTrials.gov Identifier: NCT03037632.

ImportanceCardiovascular disease contributes outsized mortality in patients from underrepresented racial and ethnic groups. Understanding levels of trust in medical researchers and knowledge of genome sequencing may help identify barriers to research participation and develop strategies to educate patients about the role of genetics in cardiovascular disease.ObjectiveTo assess racial and ethnic differences in trust in medical researchers and genome-sequencing knowledge among patients with idiopathic dilated cardiomyopathy and determine the association between trust in medical researchers and genome-sequencing knowledge.Design, Setting, and ParticipantsThis cross-sectional study conducted by a consortium of 25 US heart failure programs included patients with idiopathic dilated cardiomyopathy defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes. Enrollment occurred from June 7, 2016, to March 15, 2020.Main Outcomes and MeasuresPercent distributions, means, and associations of genome-sequencing knowledge scores and research trust scores for Hispanic, non-Hispanic Black (hereafter referred to as Black), and non-Hispanic White participants (hereafter referred to as White).ResultsAmong 1121 participants, mean (SD) age was 51.6 (13.6) years with 41.4% Black, 8.5% Hispanic, and 43.4% female. After accounting for site effects, the level of genome-sequencing knowledge was lower in Hispanic and Black participants compared with White participants (mean score difference, −2.6; 95% CI, −3.9 to −1.2 and mean score difference, −2.9; 95% CI, −3.6 to −2.2, respectively). The level of trust in researchers was lowest in Black participants (mean score, 27.7), followed by Hispanic participants (mean score, 29.4) and White participants (mean score, 33.9). Racial and ethnic differences remained after adjusting for education, age at enrollment, duration of dilated cardiomyopathy, and health status. A higher level of trust was associated with a higher level of genome-sequencing knowledge within different racial and ethnic groups.Conclusions and RelevanceIn this cross-sectional study, large racial and ethnic differences in levels of genome-sequencing knowledge and trust in medical researchers were observed among patients with dilated cardiomyopathy. Findings from this study can inform future studies that aim to enhance the uptake of genomic knowledge and level of trust in medical researchers.

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.

Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive ( BAG3 , DES , FLNC , LMNA , MYH7 , PLN , RBM20 , SCN5A , TNNC1 , TNNT2 , TTN ) or strong ( DSP ) evidence. Seven genes (14%; ACTC1 , ACTN2 , JPH2 , NEXN , TNNI3 , TPM1 , VCL ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

The Task Force has been spearheading the initiative to standardize the lexicon of cardiovascular medicine to enhance the use of clinical data, improve clinical communication, optimize quality assurance and improvement, assess outcomes, enhance process improvement efforts, and facilitate clinical research, development, and analysis of registries. Because the ACC and AHA are committed to updating existing standards as needed to maintain their currency and promote harmonization with other standards as health information technology and clinical practice evolve, this document is provided as an update of the 2005 ACC/AHA key data elements and definitions for chronic heart failure.1 The goal of this publication is to provide new data elements consistent with practice guidelines and updated terminology and attributes in compliance with current methodology of the Task Force2 and current policies of the ACC and AHA regarding harmonization of data across organizations and disciplines. Heart failure (HF) data standards are of critical importance to clinical providers, investigators, administrators, healthcare services and institutions, regulators, legislators, and payers more than ever as a result of: 1) increasing prevalence and burden of HF3,4; 2) increased focus on performance metrics for HF5; 3) increasing need for large data sets to examine comparative effectiveness and safety of treatment strategies in real world patients6; 4) increased recognition of healthcare disparities that require understanding of patient, healthcare delivery, and system variables7; 5) growing need for new effective preventive and treatment strategies in HF targeted for different stages or types of HF8; subgroups of interest and comorbidities requiring better classification and documentation of patient and treatment variables; 6) need for improved communication and for shared decision-making and transitions of care between different levels of care and providers9,10; 7) development of models for prediction of therapeutic benefit and outcomes11; 8) universally understandable data for individualization of therapies and management strategies for patients with complex HF by different providers; and 9) development and conduct of future registries, at both hospital and national levels, by providing a list of major variables, outcomes, and definitions. Approximately 6.2 million persons ≥20 years of age in the United States have HF, with approximately 1 million new HF cases diagnosed annually, and the prevalence continues to rise.3,12 Despite improvements in age-adjusted HF-related survival rates between 2000 and 2012, there has been a recent increase in mortality rates for all age and sex subgroups.12–14 HF remains as the primary diagnosis in >1 million hospitalizations annually, and the total cost of HF care in the United States exceeds $30 billion annually, with over half of these costs spent on hospitalizations.15 The mortality rates after hospitalization for HF remains high, at approximately 20% to 25% at 1 year, with similar mortality rates for heart failure with preserved ejection fraction or heart failure with reduced ejection fraction.16 The clinical syndrome of HF may result from different causes. Thus, despite a common syndrome of HF, different etiologies may imply different prognosis and varying treatment strategies, underlining the importance of specific data elements for emphasizing these differences in HF.8 Similarly, the syndrome of HF commonly overlaps with other cardiovascular diseases, such as coronary artery disease, hypertension, valvular disease, and primary myocardial disease, which are common causes of HF. Specifying these data elements for patients with HF is important for clinical care, performance improvement, research, and endpoints. Standardized data elements and definitions across studies can help accelerate and facilitate research in HF through dissemination and sharing of relevant information, comparisons, pooled analyses, and meta-analyses.17 In clinical care, a broad spectrum of clinicians provides a continuum of care for patients with HF, ranging from primary care/family medicine providers, HF specialists and/or cardiologists, cardiac and transplant surgeons, interventional cardiologists, electrophysiologists, advanced practice providers such as nurse practitioners and physician assistants, pharmacists, hospitalists, home healthcare providers, palliative care specialists and nurses, hospice specialists and nurses, social workers, and cardiac rehabilitation specialists to investigators, who must communicate with each other through a common vocabulary. Care of patients with HF may take place in specialized clinics delivered by a variety of providers previously mentioned, necessitating care coordination comprising common terminology with a patient-centered approach.18 Furthermore, HF is a chronic problem, and patients are likely to transition through different stages of HF, which requires recognition and definition of these states with common terminology standardized across different providers and encounters of care. Similarly, given the recent emphasis on quality performance measurement initiatives, particularly those for which institutions and providers are compared against each other or against benchmarks, and reimbursement strategies and penalties that are attached to such metrics, the necessity for reliable, risk adjustable, and analyzable data is gaining more importance for the professional community, as well as for payers, regulators, legislators, and consumers.5,19,20 The writing committee envisions that the data elements might be useful in these broad categories: Clinical programs, such as HF clinics, where many clinicians work together to achieve specific goals for the care and care coordination of patients with HF. Transitions of care, in which patients with HF move through different locations and levels of care (ie, inpatient, outpatient [eg, home, rehabilitation center, nursing home], palliative care, and hospice) or progress through different stages of HF (Stages A to D), with providers ranging from HF specialists, cardiac transplant physicians, home healthcare or palliative care providers, and primary care providers. Clinical registries, for ongoing care, prospective epidemiologic and comparative effectiveness research, pre- or postmarket analysis for efficacy and safety in populations of interest. Clinical research, particularly prospective randomized clinical trials where eventual pooled analysis or meta-analysis is anticipated. Quality performance measurement initiatives, provider or institutional based or external, retrospective, or prospective. Organization and design of electronic medical information initiatives, such as EHRs, pharmacy databases, computerized decision support, and cloud technologies incorporating health information. Public health policy, healthcare coverage, insurance coverage, and legislation development to provide appropriate and timely care for patients with HF and to prevent disparities in HF care. The data element tables are also included as an Excel file in the Online Data Supplement. 1.1. Special Considerations Several points are important to recognize regarding the scope of this document. First, given the magnitude of additional data elements that cardiac transplantation and mechanical circulatory support device therapies would entail, the writing group decided to focus on HF and not include cardiac transplantation and mechanical circulatory support data elements in detail in this document. Second, the data elements were not differentiated for chronic HF versus acute decompensated HF; or for inpatient, outpatient, palliative care, or hospice status, because HF is a chronic condition that is not an episodic event, and a patient can transition from one status to the other through his/her life time. The writing committee considered data elements pertinent to the full range of care provided to these patients and are intended to be useful for all care venues. Third, the data elements were not differentiated for new onset incident versus prevalent cases or number of encounters, and databases can be built and customized according to users’ needs to capture such information. Fourth, the writing committee would like to alert the readers to the existence of other documents and guidelines with which we tried to harmonize and are likely to complement the content of our document, including the “2020 AHA/ACC Key Data Elements and Definitions for Coronary Revascularization,”21 “2019 ACC/AHA/ASE Key Data Elements and Definitions for Transthoracic Echocardiography,”22 “2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials,”23 “2013 ACCF/AHA Guideline for the Management of Heart Failure,”24 “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure,”9 Centers for Medicare & Medicaid Services (https://www.medicare.gov/hospitalcompare/search.html), and The Joint Commission core HF performance measures; meaningful use criteria; The Agency for Healthcare Research and Quality's quality indicators for HF; Get With The Guidelines and National Cardiovascular Data Registry CathPCI Registry data elements. We made every attempt to use guideline- and evidence-based definitions. Finally, we did not include data element fields for entry of calculated risk scores, as databases can be programmed and customized to calculate risks scores according to the user’s objective as different risk models can be used for different purposes. The intent of this writing committee was not to be overly prescriptive.

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. Methods and results Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). Conclusions Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics was assembled to evaluate evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of the 19 genes classified as definitive, strong or moderate, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 commercially available genetic testing panels evaluated, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In a systematic curation of published evidence for genes considered relevant for monogenic DCM, 12 were classified as definitive or strong and seven as moderate evidence spanning 10 gene ontologies. Notably, these 19 genes only explain a minority of DCM cases, leaving the remainder of DCM genetic architecture incompletely addressed. While clinical genetic testing panels include most high evidence genes, genes lacking robust evidence are also commonly included. Until the genetic architecture of DCM is more fully defined, care should be taken in the interpretation of variable evidence DCM genes in clinical practice.

Background Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A‐band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Methods Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. Results Forty‐nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3’) end of the A‐band. All cardioskeletal probands had onset of proximal‐predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Conclusion Although heterozygous TTNtv in the A‐band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A‐band TTNtv who may be at risk for multisystem disease., Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Although heterozygous TTNtv in the A‐band are known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness.

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.

Background: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis. Methods: Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several SOS1 variants with potential disease involvement. As several lines of evidence have implicated dysregulated rat sarcoma signaling in the pathogenesis of DCM, we assessed functional impact of each variant on the activation of ERK (extracellular signal-regulated kinase), AKT (protein kinase B), and JNK (c-Jun N-terminal kinase) pathways. Relative expression levels were determined by Western blot in HEK293T cells transfected with variant or wild-type human SOS1 expression constructs. Results: A rare SOS1 variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band TTN truncating variant in a pedigree with aggressive, early-onset DCM. Reduced disease severity in the absence of the SOS1 variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified 5 additional SOS1 variants with potential disease involvement in 4 other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold, as well as the C-terminal REM (rat sarcoma exchange motif), CDC25 (cell division cycle 25), and PR (proline-rich) tail domains. Increased phosphorylated ERK expression relative to wild-type levels was seen for all 6 SOS1 variants, paralleling known disease-relevant SOS1 signaling profiles. Conclusions: These data support gain-of-function variation in SOS1 as a contributing factor to isolated DCM.

Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen’s MYH7 -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7 -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here. Methods: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group). Results: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands. Conclusions: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632

To describe recent advancements in cardiovascular genetics made possible by leveraging next-generation sequencing (NGS), and to provide a framework for practical applications of genetic testing for hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathies (ARVC).The availability of NGS has made possible extensive reference databases. These, combined with recent initiatives to compile previously siloed commercial and research cardiomyopathy data sets, provide a more powerful and precise approach to cardiovascular genetic medicine. HCM, DCM and ARVC are cardiomyopathies usually inherited in an autosomal dominant pattern. Over 1000 pathogenic mutations have been identified: HCM in genes encoding proteins of the sarcomere, and ARVC in genes encoding proteins of the desosome. DCM shows considerably more diverse ontology, suggesting more complex pathophysiology. In addition to allelic and locus heterogeneity, reduced penetrance and variable expressivity among affected individuals can make the clinical diagnosis of 'familial cardiomyopathy' less apparent.Current evidence supports the use of genetic testing in clinical practice to improve risk stratification for clinically affected patients and their at-risk relatives for hypertrophic, arrhythmogenic, and dilated cardiomyopathies. Understanding how to implement genetic testing and to evaluate at-risk family members, provide clinical implications of results as well as discuss limitations of genetic testing is essential to improving personalized care.

Purpose Integrating 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. Methods Expert 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. Results Adjustments 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. Conclusion These 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.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only ∼25-40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotype-phenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotype-based therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management.

Background Pathogenic variants in TTN (OMIM 188840), encoding the largest human protein, are known to cause dilated cardiomyopathy and several forms of skeletal myopathy. The clinical interpretation of TTN variants is challenging, however, due to the frequency of missense changes, variable testing and reporting practices in commercial laboratories, and incomplete understanding of the spectrum of TTN‐related disease. Methods We report a heterozygous TTN deletion segregating in a family with an unusual skeletal myopathy phenotype associated with facial weakness, gait abnormality, and dilated cardiomyopathy. Results A novel 16.430 kb heterozygous deletion spanning part of the A‐ and M‐bands of TTN was identified in the proband and his symptomatic son, as well as in an additional son whose symptoms were identified on clinical evaluation. The deletion was found to be de novo in the proband. Conclusion Pathogenic variants in TTN may be an unrecognized cause of skeletal myopathy phenotypes, particularly when accompanied by dilated 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.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment., Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and impaired contractility without an underlying ischaemic origin. DCM has heterogeneous aetiologies (including gene mutations, infections and inflammation) and clinical presentations and can eventually result in heart failure.

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health (NIH), is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen Variant Curation Expert Panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures (SOPs) for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.