Academic literature on the topic 'Hypertrophic cardiomyopathy, gene mutations, QT'

Abstract Inherited arrhythmias are disorders caused by one or more genetic mutations that increase the risk of arrhythmia, which result in life-long risk of sudden death. These mutations either primarily perturb electrophysiological homeostasis (e.g. long QT syndrome and catecholaminergic polymorphic ventricular tachycardia), cause structural disease that is closely associated with severe arrhythmias (e.g. hypertrophic cardiomyopathy), or cause a high propensity for arrhythmia in combination with altered myocardial structure and function (e.g. arrhythmogenic cardiomyopathy). Currently available therapies offer incomplete protection from arrhythmia and fail to alter disease progression. Recent studies suggest that gene therapies may provide potent, molecularly targeted options for at least a subset of inherited arrhythmias. Here, we provide an overview of gene therapy strategies, and review recent studies on gene therapies for catecholaminergic polymorphic ventricular tachycardia and hypertrophic cardiomyopathy caused by MYBPC3 mutations.

Abstract Hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are inherited diseases characterized by a wide genetic heterogeneity. Based on the separate incidence of these pathologies and on the absence of linkage, the occurrence of both diseases in the same individual has an incidence of about 1/250000. We describe a rare case report of a 24 years-old patient with maternal familiarity for type 1 LQTS (mother carrier of KCNQ1 c.1781G>A) and paternal familiarity for HCM (father carrier of TNNI3 c.592C>G mutation) who inherited both gene mutations and was diagnosed with HCM and LQTS later in adolescence, after clinical and genetic evaluations.

Abstract Aims Recently, the spectrum of background mutation in the genes implicated in sudden arrhythmic death syndrome (SADS), has been elucidated in the Caucasian populations. However, this information is largely unknown in the Asian populations. Methods and results We assessed the background rare variants (minor allele frequency < 0.01) of major SADS genes in whole genome sequence data of 1514 healthy Taiwanese subjects from the Taiwan Biobank. We found up to 45% of healthy subjects have a rare variant in at least one of the major SADS genes. Around 3.44% of healthy subjects had multiple mutations in one or multiple genes. The background mutation rates in long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy genes were similar, but those in Brugada syndrome (BrS) (SCN5A) and hypertrophic cardiomyopathy (HCM) genes (MYBPC3, MYH7, and TNNT2) were higher, compared to those reported in the Caucasian populations. Furthermore, the rate of incidental pathogenic variant was highest in MYBPC3 gene. Finally, the number of variant was proportional to the exon length of the gene (R2 = 0.486, P = 0.0056) but not related to its functional or evolutionary importance (degree of evolutionary conservation) (R2 = 0.0008, P = 0.9218), suggesting that the mutation was random. The ratio of variant number over exon nucleotide length was highest in MYBPC3, MYH7, and TNNT2 genes. Conclusion Unique features of background SADS gene mutation in the Asian populations include higher prevalence of incidental variant in HCM, BrS, and long QT 3 (SCN5A) genes. HCM genes have the highest variant number per exon length.

Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

Aims Arrhythmia mechanisms in hypertrophic cardiomyopathy remain uncertain. Preclinical models suggest hypertrophic cardiomyopathy-linked mutations perturb sarcomere length-dependent activation, alter cardiac repolarization in rate-dependent fashion and potentiate triggered electrical activity. This study was designed to assess rate-dependence of clinical surrogates of contractility and repolarization in humans with hypertrophic cardiomyopathy. Methods All participants had a cardiac implantable device capable of atrial pacing. Cases had clinical diagnosis of hypertrophic cardiomyopathy, controls were age-matched. Continuous electrocardiogram and blood pressure were recorded during and immediately after 30 second pacing trains delivered at increasing rates. Results Nine hypertrophic cardiomyopathy patients and 10 controls were enrolled (47% female, median 55 years), with similar baseline QRS duration, QT interval and blood pressure. Median septal thickness in hypertrophic cardiomyopathy patients was 18mm; 33% of hypertrophic cardiomyopathy patients had peak sub-aortic velocity >50mmHg. Ventricular ectopy occurred during or immediately after pacing trains in 4/9 hypertrophic cardiomyopathy patients and 0/10 controls (P = 0.03). During delivery of steady rate pacing across a range of cycle lengths, the QT-RR relationship was not statistically different between HCM and control groups; no differences were seen in subgroup analysis of patients with or without intact AV node conduction. Similarly, there was no difference between groups in the QT interval of the first post-pause recovery beat after pacing trains. No statistically significant differences were seen in surrogate measures for cardiac contractility. Conclusion Rapid pacing trains triggered ventricular ectopy in hypertrophic cardiomyopathy patients, but not controls. This finding aligns with pre-clinical descriptions of excessive cardiomyocyte calcium loading during rapid pacing, increased post-pause sarcoplasmic reticulum calcium release, and subsequent calcium-triggered activity. Normal contractility at all diastolic intervals argues against clinical significance of altered length-dependent myofilament activation.

Summary Objectives: Our research is a pilot study that specializes in the molecular genetic investigation of the TNNT2 gene in Czech patients with HCM/FHC disease. This study was initiated with exons 9 and 11 of TNNT2 because of their crucial role in the binding ability of cardiac troponin T to α-tropomyosin, and continued with analyses in other regions of the gene. Methods: Hundred and eighty-one Czech probands with HCM/FHC were enrolled in this study. The study group consisted of 24 families with FHC and probands without FHC history but with HCM diagnosis. The clinical diagnosis was based on echocardiography. DNA was isolated from peripheral blood lymphocytes and subsequently analyzed by the polymerase chain reaction (PCR), followed by DNA sequencing analyses, which were cross-sequenced. Results: The ΔGlu160 mutation was observed in a sequence of the TNNT2 gene in a patient with the severe form of hypertrophic cardiomyopathy. No sequence alteration was found in exons 9 and 11 of the TNNT2 gene found in the rest of the DNA samples. Conclusion: The ΔGlu160 mutation was observed in patients with severe forms of hypertrophic cardiomyopathy. This region is responsible for binding troponin T to α-tropomyosin. This mutation may lead to functional and structural effects on the troponin T protein. Mutations in this region are reported relatively rarely and therefore it was unique to observe the ΔGlu160 mutation in our study.

Abnormal balance of inward and outward ion currents in HCM ventricular cardiomyocytes determines a reduced lusitropic response to beta-adrenergic stimulation, due to insufficient APD and Ca2+ transient shortening. In HCM patients, this translates into exercise-induced QTc prolongation, TQ shortening and impaired diastolic reserve, contributing to reduced exercise tolerance. MYBPC3-related HCM showed increased long-term prevalence of systolic dysfunction compared to MHY7, in spite of similar outcome. This trend was subtended by an age-related decline in contractile performance in vitro in MYBC3 but not in MHY7 samples. Such observations suggest different pathophysiology of clinical progression in the two subsets and may prove relevant for understanding of genotype-phenotype correlations in HCM

La MCH es una de las enfermedades cardíacas hereditarias más comunes. La complejidad clínica que caracteriza a la MCH tiene su base en su heterogeneidad genética. Tras varios años de investigación, la identificación de mutaciones en 13 genes que codifican proteínas del sarcómero ha llevado a la definición de la MCH primaria como una enfermedad del sarcómero. Las mutaciones en los genes MYBPC3 y MYH7 están involucrados en la génesis de la enfermedad en aproximadamente la mitad de los pacientes índice con MCH, mientras que las mutaciones en los genes TNNT2, TNNI3, TPM1, ACTC, MYL2 y MYL3 suponen entre un 1 a un 5% de los casos. Dada la dificultad de predecir el riesgo de eventos adversos, como la MS, a partir de los datos clínicos, la investigación genética ha perseguido desde el principio determinar la relación entre el gen mutado o el tipo de mutación y la evolución de la enfermedad. Una correlación entre el genotipo y el fenotipo bien demostrada tendría implicaciones muy importantes para el tratamiento y la prevención de los eventos adversos en estos pacientes. Así en último término, los estudios moleculares y su correlación genotipo-fenotipo podrían ser herramientas útiles para ayudar al cardiólogo a tomar decisiones sobre los tratamientos a aplicar y el seguimiento individualizado de afectados y portadores asintomáticos. A pesar de los avances en el campo de la Genética, en la actualidad no hay consenso definitivo sobre el grado de determinismo asignable a las mutaciones conocidas en los diferentes genes. Por tanto, son necesarios estudios poblacionales con grandes series de pacientes a partir de los cuales poder establecer conclusiones definitivas sobre la relación genotipo-fenotipo. La información sobre genotipo-fenotipo y pronóstico de las diferentes mutaciones en el gen de la troponina T (TNNT2) es escasa y en ocasiones contradictoria, por su baja prevalencia (3-5%) en las series publicadas. Clásicamente se han relacionado las mutaciones en TNNT2 con un alto riesgo de muerte súbita (MS) en jóvenes con HVI leve. En consonancia con todo lo expuesto nos propusimos los objetivos de esta Tesis Doctoral: 1. Estudiar la penetrancia de la miocardiopatía hipertrófica en 9 familias portadoras de una idéntica mutación en el gen TNNT2. 2. Describir las variables morfológicas, clínicas y valor pronóstico de los pacientes portadores de la mutación Arg92Gln en el gen TNNT2 en nuestra serie, y comparación con las publicadas. 3. Comparar las características clínicas y pronósticas de esta población con una cohorte de pacientes con MCH no portadores de esta mutación, especialmente pacientes con otras mutaciones identificadas en TNNT2, otras mutaciones en genes sarcoméricos y pacientes con mutación no identificada. 4. Evaluar la prevalencia de mutaciones en genes sarcoméricos en pacientes con MCH de nuestra comunidad. 5. Demostrar un efecto fundador de la mutación Arg92Gln en la población de estudio. Para ello, desde noviembre del 2007 hasta febrero 2012 se evaluan 210 pacientes consecutivos no emparentados con diagnóstico de MCH. En todos los probandos se realiza estudio cardiológico completo, y se recoge muestra sanguínea para análisis genético. A los familiares de primer grado se les ofrece la realización de screening familiar consistente en evaluación cardiológica y genética (si hallazgo de mutación en el probando). En todos los pacientes se recogen una serie de variables en relación a la caracterización del fenotipo. La penetrancia de la enfermedad la determinamos en base a los criterios eléctricos y ecocardiográficos. En 8 probandos se identificó una idéntica mutación de tipo missense en heterocigosis en el gen TNNT2: Arg92Gln, localizada en el exón 9. Posteriormente se analizó la presencia de dicha mutación en los familiares, y se buscó un posible efecto fundador. Se realiza un exhaustivo análisis de resultados en cuanto a las variables clínicas y genéticas analizadas, prestando especial atención a los marcadores de mal pronóstico y/o muerte súbita en estos pacientes. Nuestro estudio concluye lo siguiente: 1. Las mutaciones en el gen de la troponina T son responsables de un 11.4% de casos de MCH en nuestra población insular, muy superior al de otras series. 2. El origen insular de la población de estudio, y la endogamia asociada habitualmente a este tipo de poblaciones, ha influido probablemente en la alta prevalencia de estas mutaciones. 3. Se constata un efecto fundador causal de los numerosos casos de MCH por la mutación Arg92Gln, localizada geográficamente en el noroeste de Mallorca, que no explica todos los casos, pero sí la mayoría. 4. La mutación TNNT2 Arg92Gln se asocia a miocardiopatía de desarrollo precoz, a menores edades que el resto de mutaciones. La probabilidad que el 50% de los portadores expresen el fenotipo se alcanza a los 37 años de edad. 5. La MCH por mutación TNNT2 Arg92Gln se caracteriza por una alta penetrancia, un alto riesgo de MS en jóvenes, en la mayoría como 1ª manifestación de la enfermedad, precisando el 38% implante de DAI como prevención primaria, con casos de MCH con hipertrofia sólo leve o moderada o en muchos otros casos con MCD al diagnóstico. 6. La mutación Arg92Gln produce alta frecuencia de fenotipo mixto: MCH con hipertrofia leve o moderada, y/o MCD, incluso dentro de la misma familia y a edades similares. Asimismo presentan disfunción sistólica en un porcentaje elevado (45%). 7. Los sujetos índice portadores de la mutación TNNT2 Arg92Gln presentan un perfil de riesgo significativamente peor comparado con el resto de pacientes con MCH y otras mutaciones o mutación no identificada. Existe una peor supervivencia libre de muerte cardiovascular asociada a esta mutación. La supervivencia media es de 54 años. A los 50 años la probabilidad de supervivencia es del 50%.

Orientação: Maria Alexandra Núncio de Carvalho Ramos Fernandes
A Miocardiopatia Hipertrófica (MH) é uma doença genética cardiovascular, ocorrendo em 1/500 indivíduos da população em geral. É considerada a principal causa de morte súbita em jovens e jovens atletas. A MH apresenta um padrão de transmissão autossómica dominante com elevada variabilidade clínica (mesmo no seio da mesma família) e genética (quer ao nível de locus quer alélica). Esta variabilidade genética influencia a magnitude da hipertrofia cardíaca e o risco de morte súbita. A maioria das mutações descritas estão associadas a genes que codificam para proteínas sarcoméricas. No entanto em mais de 40% dos pacientes com MH não se encontram mutações em genes conhecidos. Vários estudos recentes associam outros genes não sarcoméricos a casos de MH, como por exemplo, genes que codificam para proteínas envolvidas na sinalização de cálcio e nas funções auxiliares ao sarcómero cujas mutações podem ser responsáveis pelo desenvolvimento de MH, quer como genes de susceptibilidade (ACTN2, FHL1, GLA, RAF1, TTR, VCL) quer como genes modificadores (AGTR1). Neste trabalho, pretendeu-se aplicar a técnica de HRM ao diagnóstico genético de MH, analisando um grupo de 58 indivíduos, - 39 indivíduos com diagnóstico de MH sem mutações nos principais genes sarcoméricos previamente identificadas, 9 dos quais são atletas de alta competição e 19 jovens atletas sem diagnóstico de MH. Para tal, foram desenhados, optimizados e testados 14 pares de primers para a aplicação em HRM. Neste trabalho, foi possível detectar as seguintes mutações no gene ACTN2 (IVS7+34G>A, IVS7+80A>G, IVS8+23G>A) e no gene AGTR1, na região 3’UTR 1166A>C, confirmadas por SA. A técnica de HRM diminuiu drasticamente a necessidade de SA, diminuindo os custos e tempo de espera dos resultados.
Hypertrophic cardiomyopathy (HCM) is a cardiovascular genetic disorder, that occurs in 1/500 individuals in the general population and is rated as the main common cause of sudden dead in young people and young athletes. HCM has an autosomal dominant pattern of transmission, showing a high clinical variability (even in the same family) and genetics (both at locus or allelic level). This genetic variability affects the magnitude of cardiac hypertrophy and risk of sudden death. Most of the described mutations are associated with genes encoding sarcomeric proteins. However more than 40% of index patients, no mutation in known genes is identified. Several recent studies have associated non-sarcomeric genes with HCM cases, such as genes encoding proteins implicated in calcium signalling and auxiliary functions to the sarcomere – whose mutations may guide the development of the HCM -, susceptibility genes like (ACTN2, FHL1, GLA, RAF1, TTR, VCL).and modifiers genes such as (AGTR1). The aim of this work was to apply High Resolution Melting (HRM) technique in HCM genetic diagnosis, analyzing a group of 58 individuals- 39 with HCM, without previously identified mutations in the key sarcomeric genes, 9 of them young athletes and 19 healthy young athletes Therefore, 14 primer pairs were designed, optimized and tested for their use in HRM. With this study it was possible to detect the following modifications in the ACTN2 gene: IVS7+34G>A, IVS7+80A>G, IVS8+23G>A; and in the AGTR1 gene: 3’UTR 1166A>C of, confirmed by SA. The HRM technique drastically reduced the need of SA, decreasing both costs and time period for results.

Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

Hypertrophic cardiomyopathy is characterized by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading conditions (such as hypertension or valvular disease). Hypertrophic cardiomyopathy is a genetic disease, usually with an autosomal dominant inheritance. About 35–60% of patients with hypertrophic cardiomyopathy carry a pathogenic mutation in sarcomeric protein genes. Most mutations are observed in genes encoding beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3), or cardiac troponin T (TNNT2). Non-sarcomeric genetic causes exist, especially in children (Pompe disease, Noonan syndrome, or Friedreich ataxia). In adults, non-sarcomeric genetic causes include metabolic storage diseases such as Danon disease (LAMP2 gene), Fabry disease (GLA gene), left ventricular hypertrophy associated with Wolff–Parkinson–White syndrome (PRKAG2 gene), familial amyloidosis (TTR gene), and mitochondrial cardiomyopathies.

Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.

Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease, characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Most patients have both left- and right-sided heart failure which are often accompanied by severe symptoms. Enlargement of both atria is usually present and thromboembolic events are common. The prognosis is generally poor and a significant proportion of patients require a cardiac transplantation. RCM may appear in the context of diseases involving multiple organs or it may be confined to the heart. In addition, the condition appears in both familial and non-familial forms. The majority of familial forms are caused by sarcomeric gene mutations, which are also frequently identified in hypertrophic, dilated, and non-compaction cardiomyopathy. This implies that familial evaluation should be considered whenever an individual is diagnosed with RCM. In non-familial RCM, the most frequent aetiology is amyloidosis due to haematological diseases or senile forms. There are no randomized clinical trials of therapy in patients with symptomatic RCM. Diuretics remain the cornerstone of treatment and require careful titration since RCM patients are very sensitive to hypovolaemia. Since the condition is very rare with a severe disease expression and poor prognosis, it is recommended that RCM patients should be followed in expert centres in order to optimize management of the individual patient.

Genetic counselling is one of the major tools in managing inherited cardiac conditions (ICCs) including single gene disorders such as hypertrophic cardiomyopathy and long QT syndrome to multifactorial conditions such as coronary artery disease (CAD) and congenital heart disease (CHD). This chapter deals with genetic counselling for ICCs that are typically transmitted in a Mendelian fashion, for example cardiomyopathies, arrhythmias, Marfan syndrome, as well as inherited lipid disorders. Typically, a genetic counsellor works within a multidisciplinary team including cardiologists, clinical geneticists, nurses, social workers, and psychologists. This chapter covers the role of genetic counsellors, process, consent and confidentiality, communication, and outcomes.

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme. In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins. One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.