GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy

Background: Familial dilated cardiomyopathy (DCM) is a monogenic disorder typically inherited in an autosomal dominant pattern. We have identified two Finnish families with familial cardiomyopathy that is not explained by a variant in any previously known cardiomyopathy gene. We describe the cardiac phenotype related to homozygous truncating GCOM1 variants.Methods and Results: This study included two probands and their relatives. All the participants are of Finnish ethnicity. Whole-exome sequencing was used to test the probands; bi-directional Sanger sequencing was used to identify the GCOM1 variants in probands’ family members. Clinical evaluation was performed, medical records and death certificates were obtained. Immunohistochemical analysis of myocardial samples was conducted. A homozygous GCOM1 variant was identified altogether in six individuals, all considered to be affected. None of the nine heterozygous family members fulfilled any cardiomyopathy criteria. Heart failure was the leading clinical feature, and the patients may have had a tendency for atrial arrhythmias.Conclusions: This study demonstrates the significance of GCOM1 variants as a cause of human cardiomyopathy and highlights the importance of searching for new candidate genes when targeted gene panels do not yield a positive outcome.

Systems analysis of the familial cardiomyopathy signaling network

Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed a predictive model of the HCM/DCM signaling network utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8% with higher accuracy in the HCM context (90%) compared with DCM (75%). Global sensitivity analysis identified key reactions of the signaling network, with calcium activation of myofilament force development and calcium-calmodulin kinase signaling ranking the highest. We performed a structural revision analysis to identify missing interactions in HCM/DCM signaling and found some potential reactions controlling calcium regulatory proteins. Combination pharmacotherapy analysis predicted that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, and PI3K-AKT could inhibit myocyte growth in HCM. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK12 or titin or Gq protein could attenuate cardiac remodeling. The influence of existing medications on cardiac growth in HCM and DCM contexts was simulated by the model. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.

Dilated cardiomyopathy: the role of genetics, highlighted in a family with Filamin C (FLNC) variant

Dilated cardiomyopathy (DCM) is a heterogenous group of disorders characterised by left ventricular dilatation and dysfunction, in the absence of factors affecting loading conditions such as hypertension or valvular disease, or significant coronary artery disease. The prevalence of idiopathic DCM is estimated between 1:250 and 1:500 individuals. Determining the aetiology of DCM can be challenging, particularly when evaluating an individual and index case with no classical history or investigations pointing towards an obvious acquired cause, or no clinical clues in the family history to suggest a genetic cause. We present a family affected by DCM associated with Filamin C variant, causing sudden cardiac death at a young age and heart failure due to severe left ventricular impairment and myocardial scarring. We review the diagnosis and treatment of DCM, its genetic associations and potential acquired causes. Thorough assessment is mandatory to risk stratify and identify patients who may benefit from primary prevention implantable cardioverter defibrillator therapy according to international guidelines. Genetic testing has some limitations, and is positive in only 20%–35% of DCM, but should be considered in specific cases to identify families who may benefit from cascade screening after appropriate counselling. The management of often complex familial cardiomyopathy requires specialist input for every case, and the appropriate infrastructure to coordinate investigations.

Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology

The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.

Preliminary Study of Coupling Intervals of Premature Ventricular Complexes in Dogs With Different Cardiac Diseases

Coupling interval (CI), the time (ms) from the onset of a sinus QRS to the onset of the following premature ventricular complex (PVC), and their variability (CIV) might predict mortality and elucidate mechanisms of arrhythmogenesis. There has been limited investigation of CIV in dogs. Therefore, we determined CIV and prematurity index (PI) in three groups of dogs with ventricular arrhythmias that were subject to 24 hour ambulatory electrocardiographic (Holter) monitoring. Dogs in group 1 had presumptive arrhythmogenic right ventricular cardiomyopathy (ARVC), those in group 2 had structural heart disease in which patients with valvular heart disease predominated, and those in group 3 had a dilated cardiomyopathy (DCM) either phenotype or presumed familial cardiomyopathy. In this preliminary study, we did not find significant differences in indices of CIV between groups. Median PI was lower in dogs treated with antiarrhythmic therapy. Severity of cardiac remodeling, except for left atrial to aortic ratio, were not correlated with CIV. It was not possible to determine the mechanism of arrhythmias in ARVC, DCM phenotype or structural heart disease groups and re-entry, triggered activity, and abnormal automaticity are possible etiologies. The effect of antiarrhythmic therapy demonstrated potential drug effect on CIV. Risk for malignant arrhythmias and sudden cardiac death were not examined. A larger study would be needed to determine if differences exist; if present, this would give insight into possible mechanisms and optimal antiarrhythmic therapy.

Case Report: Novel Likely Pathogenic ACTN2 Variant Causing Heterogeneous Phenotype in a Korean Family With Left Ventricular Non-compaction

Left ventricular non-compaction (LVNC) is a very rare primary cardiomyopathy with a genetic etiology, resulting from the failure of myocardial development during embryogenesis, and it carries a high risk of left ventricular dysfunction, thromboembolic phenomenon, and malignant arrhythmias. Here, we report the first case of familial LVNC in Korea, caused by a novel ACTN2 missense variant. We performed duo exome sequencing (ES) to examine the genome of the proband and his father. A 15-year-old boy was admitted for the evaluation of exertional dyspnea for 2 weeks. He was diagnosed with LVNC with a dilated cardiomyopathy phenotype [left ventricular end-diastolic dimension 60 mm, interventricular septal dimension 8.2 mm by transthoracic echocardiography (TTE)]. For the screening of familial cardiomyopathy, TTE and cardiac magnetic resonance imaging (cMRI) were performed, which revealed hypertrophic and isolated LVNC in the proband's father and sister, respectively. In particular, the cMRI revealed dense hypertrabeculation with focal aneurysmal changes in the apical septal wall in the proband's father. ES of the father–son duo identified a novel heterozygous c.668T>C variant of the ACTN2 gene (NM_001103.3:c.668T>C, p.Leu223Pro; no rsID) as the candidate cause of autosomal dominant LVNC. Sanger sequencing confirmed this novel variant in the proband, his father, and sister, but not in the proband's grandmother. Even within families harboring the same variant, a variable risk of adverse outcomes is common. Therefore, familial screening for patients with LVNC associated with ACTN2 variant should be performed for early detection of the LVNC phenotype associated with poor outcomes, such as dilated LVNC.

Easily Missed: A Case Series of New Heart Failure in Young Adults

Background. While uncommon, heart failure (HF) can present in young adults from a variety of causes. Identifying HF in a young patient presents many challenges, the foremost of which is recognition of the signs and symptoms of HF. Case Summary. We present four cases of new diagnosis of HF (due to familial cardiomyopathy, tachycardia-induced cardiomyopathy, spontaneous coronary artery dissection, and peripartum cardiomyopathy) to highlight the range of etiologies and presentations requiring recognition in this patient population. Discussion. A high index of suspicion is needed to diagnose HF in young adults, who may not present with classic signs and symptoms. Young adults represent a unique patient population that differs from the older patients with HF. Young adults with newly diagnosed HF should be promptly referred to a center offering full diagnostic capabilities and advanced cardiac therapies.

The Mechanisms of the Frank-Starling Law and Familial Cardiomyopathy are Different. The Function of Myosin Binding Protein-C is Retained on Myocyte Length Increase and Force Generated is Kinase controlled

I have recently reiterated that the cross-bridge is a calcium ATPase that is inhibited by magnesium and this arises because in normal hearts Myosin binding Protein-C prevents the use of MgATP as rate limiting substrate ensuring that Ca2+ replaces Mg2+ in the excitation pathway. Here I revisit the studies on [Ca2+] dependency of ATPase and tension under diastolic stretch with a different conclusion on Hill coefficients. This reveals the underlying mechanisms of the Frank-Starling Law and Hypertrophic myopathy are not the same, the former being kinase controlled.