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Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is identified in genes encoding sarcomere proteins.
- hypertrophic cardiomyopathy
- sarcomeres
- genetic screening
1. Introduction
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, with a prevalence of 1 in 500 individuals; it is characterized by asymmetric left ventricular (LV) hypertrophy, which is not explained by an overload caused by other cardiac or systemic diseases [1,2,3]. HCM has been the focus of intense clinical and basic science investigation for decades, since the discovery of the first mutation in the Myosin Heavy Chain-7 (MYH7) gene, encoding β-cardiac myosin heavy chain (β-MHC), in 1989 [4]. Research studies conducted over the last 30 years have provided significant insights into the genetic and pathogenic basis and clinical course of HCM. Mutations in genes encoding sarcomere proteins have been identified as the main cause of HCM and the molecular mechanisms of the disease have been largely elucidated, with the consequent improvement of clinical management and the discovery of novel therapies [5]. However, despite the progress that has been made in genetic screening, the causal mutation remains unidentified in up to 60% of HCM patients [1,6].
The pathophysiologic characteristics of HCM are unexplained LV hypertrophy (LVH), left ventricular diastolic dysfunction, a high risk of arrhythmias and sudden cardiac death (SCD), and dynamic left ventricular outflow tract obstruction (LVOTO); the latter may occur in more than 50% of the patients [7]. HCM patients often present with highly variable phenotypic expressions in terms of the degree and distribution of LVH and its clinical course. It is common to observe patients who share the same gene mutation and belong to the same family to develop a variable phenotype ranging from almost asymptomatic forma to severe arrhythmias or the evolution of heart failure. The phenotypic variability can be related to genetic, epigenetic, and environmental factors. It has been shown that the HCM phenotype may be influenced by modifier gene(s), altering the effect of causal genes [8]. Furthermore, polymorphic variants in several genes may regulate wall thickness and prognosis in HCM, as shown by recent genome-wide association studies that have identified significant susceptibility loci for HCM [9] and suggest that common variants may explain some of the variable expressivity of the pathogenic sarcomere variants [10,11].
A diverse array of symptoms may occur in HCM patients, ranging from exertional dyspnea, fatigue, palpitations, lightheadedness, syncope, and atypical chest pain, to SCD [12,13]. Although a significant proportion of HCM patients remain asymptomatic or minimally symptomatic throughout life, SCD may occur in about 2% of patients as the first symptom of the disease; moreover, in about 8% of HCM patients, the disease may evolve towards heart failure with wall thinning, cavity enlargement, and systolic dysfunction [13]. Remarkably, signs and symptoms do not necessarily correlate with the degree of LVH or with the severity of LVOTO [14]. The poor correlation between the severity of symptoms and physio-pathological abnormalities and phenotypic variability might impair accurate and early diagnoses and be responsible for inappropriate therapy choices.
Determining the relationship between the genotype, phenotype, and outcomes over a lifetime is critical to improving risk stratification and to guiding patient clinical management.
2. Definitions of Sarcomeric and Non-Sarcomeric HCM
According to the results of genetic screening, HCM patients are currently categorized in two broad, relatively distinct populations: (1) the sarcomere-mutation-positive (Sarc+) group, including carriers of a sarcomere genetic mutation, which comprises about 40% of HCM patients, and (2) the sarcomere-mutation-negative (Sarc−) population, including HCM patients in whom the causal mutation has not been identified [15] (Figure 1A). In rare cases, a pathogenic variant in a non-sarcomeric gene may be identified in patients with a typical HCM phenotype: the prognosis and the clinical management of these rare cases may be assisted by the observation of the clinical course in family members and published case reports. The establishment of international registries is needed to better define the outcome and the SCD risk in this subpopulation of Sarc− HCM.
Figure 1. (A): Percentages of Sarc+ and Sarc− HCM and of phenocopies; the latter are listed in Panel (B). (C): sarcomeric genes associated with Sarc+ HCM with the relative percentages of affected individuals. The image also shows the coded pro-teins and their localization in the sarcomere. Abbreviation as in the text.
3. Differential Diagnosis with Phenocopies
Phenocopies (conditions mimicking the HCM phenotype, accounting for approximately 3–5% of unexplained LVH; Figure 1B) must be excluded from the Sarc− HCM sub-population [16]. These conditions include lysosomal storage disorders (e.g., Fabry disease), cardiac amyloidosis, glycogen storage disorders (e.g., Danon disease), protein kinase adenosine monophosphate-activated non-catalytic subunit gamma 2 (PRKAG2) cardiomyopathy, RASopathies (including Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), mitochondrial diseases, and several inborn metabolic disorders [17].
Despite being relatively less common, it is important to differentiate HCM phenocopies from both Sarc+ and Sarc− HCM because their management and prognosis differ significantly [18]. A deep understanding of the specific features of all the diseases that may cause an HCM phenotype is essential to recognizing a specific etiology [19]. Reaching a fast and definite diagnosis is crucial for the correct risk stratification of the proband and the early initiation of disease-modifying therapy (when available); moreover, the identification of the genetic causes of the disease allows for the screening of family members and the identification of additional carriers who may benefit from specific treatments [20].
The inheritance pattern and age at presentation might provide guidance for the differential diagnosis of sine causa LVH cases [19]. While rare Sarc− HCM may present as X-linked or autosomal recessive diseases, HCM typically exhibits an autosomal dominant transmission. Hence, an X-linked transmission might rather suggest a diagnosis of Anderson–Fabry or Danon disease, especially if additional signs and symptoms typical of these diseases are present, namely, acroparesthesia, gastrointestinal symptoms [21], kidney dysfunction, angiokeratomas, and anhidrosis in Fabry disease [22]; and early age of onset, muscle weakness, intellectual disability, and cardiac conduction abnormalities in Danon disease [23]. Since Sarc+ HCM is not usually associated with systemic manifestations, their presence should arouse suspicious of a different etiology. Other examples of systemic involvement are muscle weakness in mitochondrial diseases, peripheral nervous system involvement, and carpal tunnel syndrome in amyloidosis, gait disturbances in Friedreich’s ataxia, facial dysmorphism in RASopathies, and so on.
The identification of LVH in a neonate or an infant with a matrilinear inheritance is highly suggestive of a metabolic or a mitochondrial disease [19]. On the other hand, the identification of LVH in an elderly patient represents a red flag for amyloidosis, particularly when associated with a discrepancy between the EKG voltages and the degree of LVH in the echocardiogram [24].
In addition to the clinical presentation and type of inheritance, EKG abnormalities might provide important diagnostic hints: for example, in patients with massive LVH in echocardiograms, high EKG voltages associated with pre-excitation are characteristic of Danon disease [19]. Other disease-specific EKG findings are short PQ intervals in Anderson–Fabry disease and atrio-ventricular blocks in cardiac amyloidosis or storage diseases [19].
In addition to the clinical observations and EKGs, conventional and advanced imaging plays a central role in the diagnostic workup of unexplained LVH cases and often shows early abnormalities and disease-specific signs, which may lead clinicians toward the correct diagnosis. This topic is discussed in more detail in paragraph 7.
4. Genetics of Sarc+ and Sarc− HCM
HCM has classically been recognized as a disease of the sarcomere (Figure 1C) [25]. Indeed, the most frequent genetic causes of HCM are mutations in genes encoding thick filament proteins, namely, myosin heavy chain-7 (MYH7) encoding for cardiac beta-myosin heavy chain (β-MHC), cardiac myosin binding protein C (MYBPC3), Myosin Light Chains 2 and 3 (MYL2 and MYL3), and myosin heavy chain 6 (MYH6) encoding cardiac alpha-myosin heavy chain (α-MHC), with the first two accounting for more than 70% of Sarc+ cases [26]. The genes encoding thin filament components, including cardiac α-actin 1 (ACTC1) and the troponin/tropomyosin complex formed by cardiac troponin C (TNNC1), cardiac troponin I (TNNI3), cardiac troponin T (TNNT2), and tropomyosin 1 (TPM1), are associated with less than 5% of Sarc+ HCM cases [16] (Figure 1C). Furthermore, mutations in genes coding for proteins with either structural or enzymatic functions located in other structures of the sarcomere, such as the Z disc proteins Alpha-actinin-2 (ACTN2) and Myozenin-2 (MYOZ2) [27] or the M line proteins Muscle RING Finger (MuRF1), Obscurin (OBSCN) and Myomesin 2 (MYOM2), can occasionally be detected as genetic causes of Sarc+ HCM [26].
In some cases, the disease may be caused by the occurrence of more than one genetic variant: the presence of double heterozygous, compound heterozygous, and homozygous mutations is often associated with more severe disease [25]. After the introduction of next-generation sequencing (NGS), an increased number of genetic variants were detected in both sarcomere and non-sarcomere genes, allowing for the early identification of genetically affected family members and preventing the unnecessary follow-up of non-carriers. However, the NGS-based approaches have also increased the yield of variants of unknown significance (VUS), the clinical interpretation of which remains challenging [28].
According to the American College of Medical Genetics and Genomics (ACMG), a genetic variant can be considered pathogenic (P) or likely pathogenic (LP) if at least one of the following criteria is met [29]
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the genetic variant co-segregates with the HCM phenotype in the family and is absent in the phenotype-negative individuals;
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the genetic variant has prior evidence of pathogenicity, which means it has been documented as a disease-causing mutation in ≥1 patient in the published literature;
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the genetic variant is absent in the healthy population;
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the genetic variant is predicted (in silico or by functional studies) to cause major disruptions of the structure and function of the encoded protein.
In HCM, the causal mutation is often private (which means it is described only in one family) or is detected in small family pedigrees or may be a de novo variant identifiable only in the proband; moreover, HCM typically shows incomplete penetrance and variable expressivity of the phenotype, which may be due to the influence of environmental and genetic modifiers [29]. For these reasons, in many cases, the ACMG criteria cannot be used to establish the pathogenicity of genetic variants identified in HCM probands [29].
To identify the missing causal genes in Sarc− HCM, it is probably necessary to shift from a deterministic approach, which assumes that HCM is caused by a single mutation with a large effect, to a probabilistic approach, which considers HCM a polygenic disease in which multiple genetic variants with moderate effect sizes collectively contribute to the development of the phenotype (Figure 2A). Epigenetics, genetic variants with modifier effects, and responses to environmental factors are also expected to affect the expression of the phenotype (Figure 2B) [30].
Figure 2. (A): Rare variants with large effect sizes are more common in familial monogenic HCM, while those with moder-ate effect sizes and higher population frequencies are often found in the sporadic cases and in small families with oligo-genic HCM. On the other side are the common genetic variants with small size effects which in combination may pre-dispose to LVH in the presence of an overload. (B): HCM phenotypic expression is the result of the interplay of the caus-al variants with epigenetics, genetic modifiers and environmental factors (for example obesity, and hypertension).
5. HCM Caused by Mutations in Non-Sarcomeric Genes
Advances in DNA-sequencing technologies and the introduction of NGS cardiomyopathy gene panels in clinical practice allow for the rapid analysis of many genes at affordable costs, providing the opportunity to identify the missing P/LP variants in many Sarc− HCM patients [30]. Therefore, although mutations in sarcomeric genes remain the most common causes of HCM, variants in several additional genes encoding non-sarcomeric proteins have been associated with the disease in a small number of HCM patients [31]. At the present time, the genes showing strong evidence of an association with HCM are: cysteine and glycine-rich protein 3 (CSRP3) [32,33], four and half LIM domains 1 (FHL1) [34,35], filamin C (FLNC) [36,37,38], formin homology 2 domain-containing 3 (FHOD3) [39,40], junctophilin 2 (JPH2) [41], phospholamban (PLN) [42,43], Tripartite Motif-Containing 63 (TRIM63) [44,45], and Kelch-like protein 24 (KLHL24) [46].
This entry is adapted from the peer-reviewed paper 10.3390/cardiogenetics13020009
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