Cardiomyopathies denote myocardial diseases resulting from abnormalities in muscle structure and functionality, in the absence of other causes such as hypertension, valvular disease, coronary artery disease, or congenital anomalies.^1,2 Despite being initially described as rare diseases, advances in imaging technics and clinical awareness have led to an increase in its diagnosis.^3,4 Recently, cardiomyopathies have been categorized according to predominant phenotypes, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (Central Illustration).¹

Initial phenotype characterization is performed by patient’s history, family history, electrocardiogram, laboratory evaluation and cardiovascular imaging, but identifying their origins can be complicated due to shared features among various cardiomyopathies.^4,5Their heterogeneous clinical presentation and phenotypes have made genetic testing to become indispensable, offering insights into the underlying causes, assessing associated risks, and guiding potential treatment strategies.^5-7

In recent years, significant advances have been made in genetic testing.^8,9 Initially hindered by high costs, advancements in technology and the increasing availability of testing services have rendered genetic testing more accessible.⁸ Furthermore, the classification of genetic variants has improved, thanks to enhanced standardization outlined in the 2015 guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP).⁹ These advancements facilitate early detection of cardiomyopathies, enabling interventions such as lifestyle modifications, anticoagulation therapy, medication regimens, and other interventions aimed at mitigating patient risk.^1,3 In fact, recent guidelines recommend a genetic test for all patients with a cardiomyopathy.¹ The following review aims on helping the cardiologist in the understanding of the genetic variants underlying the different cardiomyopathies.

HCM is a monogenic disease with autosomal dominant inheritance characterized by ventricular hypertrophy caused by variants in several sarcomeric genes.¹² HCM is characterized by left ventricular outflow tract obstruction in 40% of patients.^12,13 Exercise intolerance, chest pain and syncope are clinical manifestations related to HCM, whereas atrial fibrillation is the most common arrhythmia.¹² Although a rare event, SCD has been associated with HCM especially in the young.^1,14 The most recent data from the National Center for Catastrophic Sports Injury Research indicate that HCM is responsible for 16.2% of deaths related to cardiovascular diseases in young athletes in the United States.¹⁵

CLINGEN, a collaborative study group funded by the NIH, identified that of the 33 genes most involved in the etiology of HCM, only 8 (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3) have definitive evidence, 3 (CSRP3, TNNC1, and JPH2) have moderate evidence, and the remaining genes have limited to no evidence supporting an association with the disease.¹⁶ Delving a little deeper into genetic epidemiology, we can affirm that the MYH7 genes (which encode heavy chain beta myosin) and MYBPC3 (which encode myosin-binding protein C) are responsible for the majority of cases.^17,18 In general, the sensitivity of genetic tests for the identification of the etiology in familial HCM revolves around 30% to 60% of cases.¹ The incomplete gene penetrance and genetic heterogeneity results in variable disease expression.¹⁹ Among clinically unaffected individuals harboring a likely pathogenic or pathogenic variants, diagnosed as part of the familial genetic cascade, 46% developed HCM in a 15-year follow-up study, highlighting a moderate disease penetrance.²⁰

HCM prognosis may also be affected by the genetic status. The SHARE registry studied 4,591 patients with HCM and observed that adverse events (ventricular arrhythmia, heart failure, and atrial fibrillation) were more frequent in patients with pathogenic sarcomeric variants.²¹ These findings have supported the use of genetic tests in risk stratification by the European Society of Cardiology Treatment of ventricular arrhythmias and prevention of sudden death.²²

DCM is defined as left ventricular or biventricular dilation of systolic dysfunction not explained by valvular disease or significant coronary artery disease.²³ The etiology of the disease is highly heterogeneous and in a significant proportion of patients no cause can be found and a genetics involvement could be associated.^23,24 A plausible genetic etiology can be identified in 10 to 40% of the cases according to clinical characteristics.²⁵

Molecular genetics became essential in the evaluation of DCM.²³ The advent of next-generation sequencing has facilitated its widespread adoption, significantly advancing our understanding of the genetic basis of DCM.²⁴ Numerous genes have been implicated in DCM and exhibit association with various phenotypic presentations.²⁶ The most common inheritance is autosomal dominant, but autosomal recessive, X-linked, mitochondrial inheritance and de novo mutations are also observed.²⁴ The penetrance is variable depending on the type of mutation and, in mainly cases, its age-dependent.^23,26-28 Gene-environment interaction, caused by myocarditis, pregnancy, chemotherapy or alcohol, can lead to phenotypic expression in patients with DCM genetic mutations.^29,30 The pre-test probability of identifying a causative gene variant for DCM may change according to specific clinical characteristics. Skeletal myopathy, family history of DCM, low voltage on the electrocardiogram, absence of hypertension and absence of left bundle branch block are all associated with the presence of a pathogenic DCM variant.²⁵

Mutations can occur in different DCM genes that encode a range of cellular mechanisms.³¹ These include genes involved in cytoskeletal, sarcomeric, desmosomal, nuclear membrane, mitochondrial and RNA-binding proteins.^1,26 The TTN is the largest protein in humans and the most common gene associated with DCM and encodes titin protein.²⁷ In the heart, it is associated with the regulation of sarcomere contraction.²⁸ It typically displays an autosomal dominant pattern of inheritance and accounts for approximately 15-25% of familial DCM cases.^27,28,32 TTN mutations in DCM are mainly truncation.²⁸ Furthermore, two thirds of genetic variants in peripartum cardiomyopathy are found in the TTN gene.²⁹ Missense TTN variants have been reported in ARVC and in skeletal myopathies.^33,34 LMNA mutations contribute for approximately 8% of genetic DCM and the most common inheritance is autosomal dominant.¹ The LMNA gene encodes lamin A/C. The main characteristics of its mutation in DCM is dysrhythmias.^23,35 Affected individuals are prone to conduction abnormalities, atrial and ventricular arrhythmias and SCD, with an annual rate of 5 - 10%.^1,35,36 Other phenotypic alterations are elevated serum creatine kinase levels and skeletal muscle involvement, such as Emery-Dreifuss muscular dystrophy.^1,23 The RBM20 mutations are presented in 1 - 5% of genetic DCM.¹ This gene encodes the RNA-binding motif 20, and the phenotypic expression associated with RBM20 mutations bears similarity to variants in the TTN gene.^37,38 The SCN5A gene encodes sodium ion channels.³⁹ Missense mutations within it can predispose individuals to DCM with an increased risk of arrhythmias, being also associated with Brugada and long QT syndrome.^1,39,40

Various other genes have been linked to DCM.¹ Mutations in genes encoding for sarcomere (MYH7, MYBPC3, ACTC1, TNNT2, TPM1), some of which are also associated with HCM or left ventricular hypertrabeculation.^1,31,41 Cytoskeleton genes (DES, DMD, FLNC, NEXN, LDB3) that include mutations in dystrophin may also express with a DCM with peripheral muscular dystrophy and arrhythmias.^42-44

Changes in therapeutic management resulting from genetic testing relies mainly on the indications for device implantation. Patients with high-risk gene mutations for SCD (LMNA, RBM20, PLN, FLNC-truncating) should be considered for ICD implantation for primary prevention even if the left ventricular ejection fraction exceeds 35%. This recommendation is particularly pertinent in the presence of additional risk factors (non-sustained ventricular tachycardia, male sex, significant late gadolinium enhancement in the cardiac magnetic resonance).¹³

Due to the new imaging and molecular techniques, the knowledge about cardiomyopathies has increased substantially over the last decades.⁴ These new phenotypic descriptions created the need for new classification, to simplify terminology and standardize diagnosis and treatment. The most recent ESC statement endorsed the proposal of replacement of the previous term ‘hypokinetic non-DCM’ for the broader term NDLVC which incorporates what has been previously described as arrhythmogenic left ventricle cardiomyopathy (ALVC), non-dilated hypokinetic cardiomyopathy, left-dominant arrhythmogenic right ventricle cardiomyopathy and the cases of arrhythmogenic DCM which do not fulfill criteria for ARVC.^1,45 NDLVC phenotype is defined as the presence of non-ischemic LV scarring or fatty replacement regardless of the presence of global or regional wall motion abnormalities, or isolated global LV hypokinesia without scarring unexplained by abnormal loading conditions or coronary artery disease.^1,45 Tissue characterization is, therefore, usually key to the diagnosis and it is assessed by cardiac magnetic resonance (CMR) including T2-weighted sequences, T1 mapping and late gadolinium enhancement.^1,46 LV systolic dysfunction is defined by the presence of an ejection fraction < 50% detected preferably by echocardiogram or CMR.^1,47

Because NDLVC is a recently described entity, its genetic background is not well established yet.¹ Genes currently associated to NDLVC are part of the phenotypic spectrum the condition is understood to comprise, thus often overlapping with DCM and ARVC.^45,48 Desmoplakin (DSP), Filamin C (FLNC), Desmin (DSM), Lamin A/C (LMNA) and Phospholamban (PLN) are the most related genes with NDLVC.^1,49,50 Elucidating genetic etiology is potentially helpful in predicting prognosis, differentiating diagnosis, and guiding therapy e.g implantable cardiac defibrillator (ICD) implantation.²² LMNA and FLNC-related cardiomyopathies present a rate of 5-10% of SCD each year, while PLN and DSP are right down the list presenting with a 3-5% SCD rate per year.^1,51 Also, genetic counseling and family screening might impact patients’ and family members’ clinical follow-up and life-changing decisions. Therefore, genetic testing is recommended in all patients identified with a NDLVC phenotype.¹ In genotype-positive phenotype-negative individuals clinical management is still challenging, as well as the precise application of family cascade screening. Further studies are needed to elucidate remaining topics.

ARVC is a rare, genetic disorder that is characterized by the replacement of the myocardium, specifically in the right ventricle, with fibrofatty tissue.^1,70-72 This pathological transformation leads to highly arrhythmogenic clinical presentations not explained by ischemic, hypertensive, or valvular heart disease.⁷¹ Although most commonly affects the right ventricle, some cases may present with a left-predominant form.^71,72 Therefore, some authors refer to this entity as arrhythmogenic cardiomyopathy.⁷¹ Clinical presentation may occur between the second and fifth decade of life by ventricular arrhythmias and SCD.^71,72

The genetic underpinnings of ARVC are often associated with mutations in desmosome-specific genes in 60% of cases.^1,73 Desmosomes are intercellular junctions that are necessary for myocyte stability and integrity.⁷¹ The major components of the desmosome include Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), Desmocollin-2 (DSC2), Desmoplakin (DSP), and Plakoglobin (JUP).^1,73 Although several genes are involved, most cases are caused by pre-mature termination of protein or abnormal splicing of the PKP2 gene.^73,74 Mutations in these genes, usually in autosomal dominant pattern and incomplete penetrance, can lead to defective mechanical bonds that hold heart cells together.^71,74 Desmosome mutations have been associated with some clinical caveats such as inverted anterior pre-cordial T-waves (V1-V3), family history and early onset of the disease with the presence of a causative mutation.⁷⁵ However, other genes related to other cardiomyopathies may also present with ARVC phenotype such as TTN, LMNA, PLN, SCN5A, and FLNC.¹ Patients carrying multiple mutations may be more prone to present with ventricular arrhythmias, suggesting a gene-dosage effect in ARVC.⁷⁶

The molecular mechanisms of ARVC are complex, and the genetic architecture is ever-evolving.^1,73,75 Given this, multidisciplinary patient care for the incorporation of genetics and family cardiovascular care is critical. Future work will refine the understanding of gene-specific outcomes in ARVC and implications for tailored therapy.

The pivotal role of genetics in cardiomyopathies cannot be overstated. Through extensive research and technological advancements, genetic factors have emerged as key determinants in shaping the phenotype of cardiomyopathies. By elucidating the genetic underpinnings, clinicians can better establish accurate diagnoses, leading to more tailored and precise treatment strategies. Furthermore, the evolving landscape of genetic knowledge continues to revolutionize therapeutic approaches, with targeted interventions aimed at mitigating specific genetic abnormalities. Thus, integrating genetic insights into clinical practice not only enhances our understanding of the cardiomyopathies but also holds tremendous promise in optimizing patient care and outcomes.