DCM is characterized by dilation of the left ventricle and reduced ejection fraction that is unexplained by secondary causes such as myocardial ischemia, arterial hypertension, or primary valve and congenital heart diseases.^1,2,5-7 Its prevalence ranges between 1 in 250 to 1 in 500 in the broader population.^7,8 Inherited and sporadic DCM must be differentiated. For instance, hereditary DCM is when ≥ 2 members of the same family meet the criteria for DCM, or when the proband has a first-degree relative who died suddenly before 35 years of age or whose DCM was confirmed through autopsy. Genetic testing is more fruitful in hereditary DCM scenarios.^7,9-11

DCM has many causes, both genetic and environmental.^2,6 These include genetic variants, toxin exposure, infections, autoimmune responses, storage diseases, and tachyarrhythmias. Monogenic variants associated with DCM have remarkable diversity, involving multiple genes and multiple biological pathways. Disease modifiers can worsen the DCM phenotype, such as epigenetic factors and acquired modifiers, including pregnancy, hypertension, and excessive consumption of alcohol and other toxic substances.^2,6,12 Various genetic factors may play a role, and it is essential to consider the interplay between genetic and acquired causes during diagnosis.^2,13-15

Selecting the right test is paramount. Given the variety of genes linked to DCM, whole exome or specific panel sequencing can be used. While whole exome sequencing could offer a broader analysis, a specialized cardiomyopathy panel ensures focus on DCM-related genes. Whole exome sequencing analyzes a large number of genes, including genes unrelated to cardiac pathologies, and could lead to secondary findings, for which the assistance of a geneticist is instrumental. The cardiomyopathy panel consists of DCM-related genes and is available in different configurations^16,17 (Table 1).

Table 1

DCM
TTN	TNNT2	ACTN2
BAG3	DES	JPH2
DSP	DMD	NEXN
FLNC	PLN	TNNI3
LMNA	SCN5A	TPM1
MYH7	TNNC1	VCL
RBM20	ACTC1
HCM
MYBPC3	TNNT2	MYL2
MYH7	TPM1	MYL3
TNNI3	ACTC1	CSRP3
TNNC1	JPH2
ACM
PKP2	DES	TGFB3
DSP	LMNA	TTN
DSG2	TMEM43	CDH2
DSC2	PLN	SCN5A
JUP	CTNNA3
Amyloidosis
TTR
Rare Cardiomyopathies
PRKAG2	LAMP2	GLA
GAA

RASopathies (BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, SOS2, LZTR1, MAP2K2, HRAS, SHOC2, PPP1CB, NF1, SPRED1, SPRED2, CBL, A2ML1) DCM: dilated cardiomyopathy; ACM: arrhythmogenic cardiomyopathy; HCM: hypertrophic cardiomyopathy.

The current genetic testing yield for DCM varies from 15% to 40%.⁵ A recently proposed scoring system, the Madrid score, can estimate the likelihood of pathogenic variants in DCM. This score considers the presence of skeletal myopathy, family history of DCM, electrocardiogram voltage, history of hypertension, and an absence of left bundle branch block in electrocardiography. When ≥ 4 of these factors are present, the test’s positivity rate can reach 79%. However, the absence of such variants does not nullify DCM diagnosis or risk among close relatives.¹⁸ Nevertheless, only selected cases should undergo genetic evaluation.^4,5

Genetic insights can profoundly influence DCM management, assisting in differential diagnosis, prognosis, and personalized treatment. Patients carrying pathogenic or likely pathogenic variants often experience worse clinical outcomes, particularly concerning malignant arrhythmias and severe heart failure.¹⁹ Some of these variants, such as those in PLN, LMNA, FLNC, TMEM43, DSP, and RBM20, with other risk factors, can support the use of implantable cardioverter defibrillators as a primary preventive measure.^2,3 Moreover, these variants have been associated with a lower likelihood of reverse cardiac remodeling, even when optimal clinical treatments are provided.¹⁹ In certain instances, genetic testing identifies a genocopy, such as TTR-related amyloidosis or arrhythmogenic cardiomyopathy (ACM), requiring alternate clinical approaches and specialized treatment.^20,21

Genetic analysis also influences detection rates among first-degree relatives. It can uncover individuals at risk of DCM or those who already have the disease but no evident symptoms. Among patients who received a heart transplant due to DCM, a study discovered pathogenic or likely pathogenic variants in 39.6% of their family members. Notably, 52.6% of these family members showed no clinical manifestations of the disease.²² Timely identification of DCM in a family is crucial, since it facilitates early intervention, which prevents disease advancement and reduces the risk of sudden death.^5,7,23

HCM is characterized by abnormal heart wall thickening due to genetic factors, excluding secondary causes like hypertension, amyloidosis, intense physical exercise, metabolic disorders, and heart valve diseases. Hypertrophy, the enlargement of the cardiac muscle, predominantly occurs in the septal wall. It is asymmetric in up to 95% of cases, but it can also be evenly distributed (symmetric hypertrophy), although the septal variant is more common. In approximately 75% of patients, this condition can lead to partial obstruction of left ventricle blood flow during rest or when induced by the Valsalva maneuver.^24,25

Because the term HCM has been used interchangeably with other nomenclatures in the past, genuine HCM must be distinguished from conditions with similar symptoms. In the 6 decades since HCM was first clinically described, the disease has been referred to by various names, including idiopathic hypertrophic subaortic stenosis and obstructive HCM. Given that obstruction of the left ventricular outflow tract is evident or emerges in the majority of HCM patients but remains absent in approximately one-third, the consensus is to use HCM to denote cases both with and without left ventricular outflow tract obstruction. Using HCM when there is left ventricular wall thickening due to systemic conditions or secondary causes of ventricular hypertrophy can be misleading. Systemic conditions encompass a range of metabolic and multisystemic disorders, including RASopathies (linked to variants in RAS-MAPK signaling pathway), mitochondrial myopathies, glycogen/lysosomal storage diseases in children, and conditions like Danon disease, amyloidosis, and Fabry disease in adults. While the extent and pattern of left ventricular wall thickening in these conditions might mirror that of isolated HCM due to sarcomeric gene variations, the underlying mechanisms, progression, and therapeutic approaches differ. Therefore, it is essential to recognize that cardiac or systemic diseases which can lead to ventricular hypertrophy should not be classified as HCM.^24-26

Further investigation of cardiomyopathies requires an imaging test, such as echocardiography, but cardiac magnetic resonance imaging is the gold standard (Figure 1). Diagnostic challenges can arise in various situations, particularly conditions that lead to secondary ventricular hypertrophy, which may resemble HCM. Examples of such conditions include heart remodeling due to athletic training ("athlete's heart") and morphological alterations stemming from chronic systemic hypertension (hypertensive cardiomyopathy). Furthermore, left-sided obstructive abnormalities, whether due to valvular or subvalvular stenosis, or even gradients secondary to non-pathological situations, such as a sigmoid-shaped septum, can also create diagnostic ambiguities.

Figure 1

While it is challenging to conclusively exclude HCM in these scenarios, a combination of clinical indicators and testing methods can help distinguish HCM from physiologically-induced ventricular hypertrophy.²⁷

HCM is generally inherited in a Mendelian pattern, primarily as an autosomal dominant trait.²⁸ For individuals suspected of HCM, advanced sequencing techniques, such as genetic panels, are advised. These panels typically include at least the 8 primary sarcomeric genes, with MYH7 and MYBPC3 being particularly significant, since they comprise approximately 70% of diagnosed cases. This approach often reveals pathogenic or likely pathogenic variants identified as disease-causing in roughly 30% of sporadic cases and 60% of family cases. Notably, certain variants in genes such as TNNC1 and others not directly linked to the sarcomere, such as CSRP3, JPH2, ALPK3, and FHOD3, have been highlighted due to the moderate-to-strong evidence of pathogenicity.¹⁶ It is crucial that competent medical laboratories or teams assess the pathogenicity of this genetic variant, and such assessment should adhere to American College of Medical Genetics and Genomics standards. Specifically for the MYH7 gene, there is an adapted pathogenicity classification system overseen by a ClinGen expert panel. The test yield is roughly 60%, and the disease penetrance is estimated at around 80%.²⁹

ACM is a genetic disorder characterized by cardiomyocyte death and fibro-fatty replacement. Myocardial scarring increases the risk of sudden cardiac death, particularly in youth and athletes.^2,30 Previously described only in the right ventricle, new insights have changed our understanding of the disease, and it is now recognized that ACM can also affect the left ventricle or both ventricles simultaneously, leading to the broader term “arrhythmogenic cardiomyopathy”.²¹

Patients with ACM can present a heterogeneous range of clinical symptoms, from asymptomatic to sudden cardiac death or severe heart failure requiring heart transplantation. Some ACM presentations can mimic myocarditis, with symptoms such as chest pain, electrocardiographic changes, and increased troponin levels, despite no obstructive coronary disease. The diagnostic criteria for the form with predominant right ventricle involvement are based on the 2010 International Task Force criteria for arrhythmogenic right ventricle cardiomyopathy.³¹ However, these criteria lack the necessary sensitivity and specificity to diagnose the form with predominant left ventricle involvement. The 2020 international (Padua) criteria for ACM updated the imaging and structural criteria for the right-dominant form and introduced new criteria for the left-dominant form. Diagnosing the left-dominant form requires confirmation of a related pathogenic or likely pathogenic variant.³²

Several genes, primarily those that encode cardiac desmosome proteins, are linked to ACM. These include PKP2, DSP, DSG2, DSC2, and JUP. ACM can also be linked to non-desmosomal genes, such as PLN, FLNC, DES, TMEM43, and LMNA.^21,33 Genotype-phenotype studies suggest that genes such as DSP, PLN, and FLNC are often associated with left-dominant ACM, while genes like PKP2, DSC2, and DSG2 are typically associated with right-dominant ACM.^16,21

For patients in whom a pathogenic ACM variant is identified, genetic screening for first-degree relatives is recommended.² Recognizing pathogenic or likely pathogenic variants in relatives is crucial because strenuous physical activity must be restricted in these patients, given the association with early symptom onset and increased arrhythmic burden.^2,34,35

Patient risk should be stratified according to specific guidelines to determine the need for a cardioverter defibrillator, thus reducing the risk of sudden death. For patients with pathogenic variants in PLN, FLNC, or LMNA and an LVEF < 45%, early cardioverter defibrillator implantation may be considered due to the high risk of sudden death.²¹

RCM is characterized by a pattern of increased ventricular filling pressure, even in small volumes, which is attributed to increased myocardial stiffness. This condition may manifest as uni- or biventricular diastolic or systolic dysfunction. Biatrial enlargement commonly presents as a notable feature of RCM. Individuals with end-stage hypertrophic or DCM can also present restrictive physiology, with the preferred terms being “HCM” or “DCM with restrictive physiology.”' Restrictive physiology can also arise from pathologies such as fibrosis, fibroelastosis, and thrombosis, which adversely affect diastolic function.^1,2

Although its exact prevalence is still unknown, it is likely the least common type of cardiomyopathy.^1,36 RCM may arise idiopathically, manifest as a family condition, or result from systemic disorders such as amyloidosis, sarcoidosis, carcinoid heart disease, scleroderma, or anthracycline toxicity.³⁶

Familial RCM is frequently characterized by autosomal dominant inheritance. In some families, this inheritance pattern is linked to mutations in the troponin I gene (TNNI3) and other sarcomeric subunits, including troponin T (TNNT2), α-actin (ACTC), and B-myosin heavy chain (MYH7). Alternatively, in certain cases, familial RCM is associated with conduction defects stemming from mutations in the desmin gene, typically involving skeletal myopathy. In rare cases, familial RCM may have an autosomal recessive inheritance pattern, as observed in conditions such as hemochromatosis due to mutations in the HFE gene or glycogen storage diseases, such as Danon disease and protein kinase, AMP-activated, noncatalytic, gamma 2 subunit cardiac (PRKAG2) syndrome. X-linked inheritance, such as in Anderson-Fabry disease, is another rare association with familial RCM.^1,36

Moreover, restrictive ventricular physiology can result from endocardial pathologies, including fibrosis, fibroelastosis, and thrombosis, thereby compromising diastolic function. The fundamental therapeutic approach is based on treating an identified cause, combined with traditional heart failure management. Advances in interactive genomic analysis and biomarkers, such as transcriptome and microRNAs, have enabled the characterization of different phenotypes, providing valuable information about treatment options and prognosis.³⁶

Systemic amyloidosis involves the extracellular deposition of fibrillar proteins. These proteins, when stained with Congo red, have emerald green birefringence under polarized light and can be found in multiple organs, including the heart and nervous system.³⁷

Once deemed rare, cardiac amyloidosis is being detected with increasing frequency as diagnostic methods evolve. Some studies show that 13% of patients with heart failure with preserved ejection fraction and 25% of autopsied older adults show amyloid transthyretin (ATTR) deposits in the heart. In other words, it is a relevant and underdiagnosed disease. Significant treatment advancements have also emerged with the discovery of novel disease-modifying medications.²⁰

Although over 30 proteins can induce amyloidosis, only 9 lead to cardiac manifestations. Of these, the immunoglobulin light chain and ATTR types account for the majority of cardiac amyloidosis cases.³⁷

Immunoglobulin light chain amyloidosis is a hematologic clonal disease in which abnormal plasma cells or B lymphocytes produce immunoglobulin light chains,³⁸ which is not the focus of this article.

The ATTR form is characterized by a misfolding of TTR, a protein that transports thyroxine and retinol. This misfolding can occur due to mutations in the TTR gene, leading to the variant form (ATTRv). In wild-type ATTR, the amino acid sequence is normal, but the wild-type protein becomes unstable for unclear reasons, likely related to aging, leading to aggregation into amyloid fibrils.^20,37

ATTRv is due to variants in the TTR gene. Over 140 TTR variants have been documented, with most being pathogenic and having autosomal dominant inheritance.³⁹ Clinical manifestations affecting the heart and nervous system, age of onset, and geographical distribution vary based on the specific variant (Table 2).⁴⁰ In the United States, the most common variants are Val142Ile, Thr80Ala, and Val50Met, while Val50Met, Val142Ile, and Glu89Gln are the most frequent worldwide. Although the worldwide prevalence of Val142Ile is higher than that of Val50Met, the penetrance of Val30Met appears to be higher, making the incidence of Val50Met-related cardiac ATTRv amyloidosis higher. The predominant phenotype of the Val142Ile variant is cardiac, with manifestations such as left ventricular hypertrophy, RCM, heart failure, atrial fibrillation, and conduction disorders. However, approximately 60% of these individuals also present with sensory neuropathy. Patients with Val50Met and early disease onset predominantly present with polyneuropathy, but those with later onset also often have cardiomyopathy. Leu131Met and Ile88Leu are variants reported in Denmark and Italy, respectively, and present with a predominantly early-onset cardiac phenotype and a more severe course.⁴¹

Table 2

Pathogenic variant in TTR gene (NM_000371.4)	Geographic distribution	Prevalence	Age onset	Phenotype	Penetrance	Survival
Val50Met	Portugal, Spain, France, Switzerland, Sweden, Germany, Japan, and Brazil	Most common world-wide variant, prevalence can approach 1:1000 in endemic areas	30–40 years in endemic areas, 50–60 years in nonendemic areas.	Cardiomyopathy: 26.9% Sensory neuropathy: 89.5% Motor neuropathy: 38.9% Autonomic neuropathy: 69.3%	Variable according to geographic locale and age at disease onset	Death within 10 to 20 years of disease onset
Val142Ile	Western Africa, USA, Caribbean, and Europe	3–4% of African-Americans	>65 years	Cardiomyopathy: 96.6% Sensory neuropathy: 60.3% Motor neuropathy: 19% Autonomic neuropathy: 27.1%	Low, but undefined and age-dependent	Death within 5-6 years of disease onset
Thr80Ala	Appalachia (USA), UK, Ireland, and Japan	1% North-west Republic of Ireland	>60 years	Cardiomyopathy: 90.5% Sensory neuropathy: 80% Motor neuropathy: 25% Autonomic neuropathy: 40%	Low penetrance	Death within 6.6 years of disease onset
IIe88Leu	Central-northern Italy	Unknown	>60 years	Cardiomyopathy: ~100% Carpal tunnel syndrome: 42% Peripheral neuropathy: <10%	Unknown	Unknown
Leu131Met	Denmark	Unknown	>30 years	Cardiomyopathy: 100% Carpal tunnel syndrome: common	Unknown	Unknown

Genetic testing must be performed for all ATTR amyloidosis patients, since the results influence diagnosis, prognosis, treatment, and family screening.^40,42 Genetic counseling should be offered, including explanation of the implications and an offer to test immediate relatives.⁴³

Clinical monitoring of at-risk patients (ie, those with a pathogenic TTR gene variant but no manifestation of disease) is primarily guided by expert recommendation. Once this gene variant is identified, forecasting the onset of the disease relies on both populational data and family trends.⁴² Clinical monitoring should begin a decade prior to the anticipated age of disease onset (≤ 60 years, depending on family history), including annual assessment. This interval can be reduced for variants known to progress more rapidly.⁴⁴ Initial tests typically include electrocardiography, transthoracic strain-imaging echocardiography, cardiac magnetic resonance, pyrophosphate scintigraphy, and certain lab tests, such as BNP, troponin, renal function assessment, as well as serum and urinary protein electrophoresis. For patients with specific variants like Thr80Ala and Val50Met, neurological evaluation with baseline electroneuromyography might be beneficial. Subsequent visits should include clinical evaluation (focused on neuropathy assessment) and electrocardiography. Other tests can be determined based on patient needs.^42,43 If changes indicating disease progression are observed in clinical or supplemental tests, treatment options must be promptly evaluated. However, for asymptomatic patients who only possess the gene variant and show no signs of disease, targeted treatment is not recommended due to a lack of evidence regarding its efficacy and safety.^40,42

Rare cardiomyopathies encompass a diverse array of phenotypes that resemble ‘classic’ morphologic subgroups such as HCM, DCM, ACM, RCM, and non-dilated left ventricular cardiomyopathy. Notably, these differ substantially in causation, pathophysiology, risk stratification, and therapeutic approaches.²

The term “phenocopies” denotes conditions that outwardly mirror the presentation of another disorder yet stem from distinct pathophysiological roots. While often used to describe any cardiomyopathy-like condition with a differing etiology, its core definition, albeit debated, refers to non-genetic diseases with phenotypes akin to genetic disorders. In HCM, for instance, phenocopies may include acquired conditions such as hypertensive heart disease, athlete's heart, or myocardial hypertrophy due to aortic stenosis. Interestingly, the European Society of Cardiology has designated genetically-based phenocopies as "genocopies".²

Accurate identification of a cardiomyopathy's etiology profoundly influences patient management and prognosis, especially when targeted treatments exist.⁴⁵ Establishing a “phenotypic diagnosis” requires delving deeper for a precise etiological diagnosis. This involves spotting diagnostic red flags, with age being a primary indicator for rare cardiomyopathies.⁴⁶ Here, symptoms, family history, complementary examinations, and, especially, genetic testing, guide this diagnostic journey.

Comprehensive diagnostic assessment requires a 3-generation pedigree to determine inheritance patterns. DCM, for instance, can involve different inheritance patterns, such as autosomal dominant, X-linked, autosomal recessive, and matrilineal. Physical examinations should monitor for signs such as hepatomegaly, ataxia, muscle weakness, and scoliosis. Routine laboratory evaluations can help pinpoint systemic causes, including assessing serum creatinine, creatine phosphokinase enzyme, myoglobinuria, transaminases, and blood lactate. For instance, elevated creatine phosphokinase levels may indicate glycogen storage disorders or muscular dystrophies, such as Duchenne, Becker, and Emery-Dreifuss, while proteinuria hints at Anderson-Fabry disease.⁴⁷ Muscular dystrophies (Duchenne, Becker, and Emery-Dreifuss) often correlate with DCM, including a heightened risk of atrioventricular block and ventricular arrhythmias.⁴⁸ Electrocardiography findings might show ventricular preexcitation in mitochondrial disorders or Pompe disease, high-amplitude QRS complexes in Pompe disease, or right-axis deviation indicative of RASopathies. In children, significant symmetrical left ventricular hypertrophy could suggest metabolic or storage disorders. When concentric left ventricular hypertrophy is combined with systolic dysfunction, it indicates potential underlying conditions, such as storage disorders, mitochondrial anomalies, or metabolic disorders, including beta-oxidation disorders.⁴⁹