Pathogenic genes and clinical prognosis in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiomyopathy characterized by left ventricular hypertrophy. It is one of the chief causes of sudden cardiac death in younger people and athletes. Molecular-genetic studies have confirmed that the vast majority of HCM is caused by mutations in genes encoding sarcomere proteins. HCM has a relatively wide phenotypic heterogeneity, varying from asymptomatic to sudden cardiac death, because of the many different mutations and pathogenic genes underlying it. Many studies have explored the clinical symptoms and prognosis of HCM, emphasizing the importance of genotype in evaluating patient prognosis and guiding the clinical management of HCM. To elaborate the main pathogenic genes and phenotypic prognosis in HCM to promote a better understanding of this genetic disease. Retrospective analysis of literature to evaluate the association between underlying gene mutations and clinical phenotypes in HCM patients. As sequencing technology advances, the pathogenic gene mutation spectrum and phenotypic characteristics of HCM are gradually becoming clearer. HCM is a widespread inherited disease with a highly variable clinical phenotype. The precise mechanisms linking known pathogenic gene mutations and the clinical course of this heterogeneous condition remain elusive.

Key Words: Hypertrophic cardiomyopathy; Genotype; Phenotype; Pathogenic genes; Prognosis

Core Tip: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiomyopathy with a highly variable clinical phenotype. This paper provides a detailed reference on the pathogenic genes of HCM and their phenotypic prognosis. These findings hold significant potential for guiding clinical decision-making, particularly in personalizing management strategies for HCM patients.

INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is a common genetic cardiomyopathy inherited in an autosomal dominant pattern, with offspring having a 50% chance of inheriting the same pathogenic genetic variant[1]. The prevalence of HCM in young adults has been estimated to be 1:200-1:500, though when considering asymptomatic HCM in the general population, the true burden is probably much higher[2-4]. Clinical manifestations of HCM can range from completely asymptomatic to typical symptoms, such as chest pain, shortness of breath, dyspnea, palpitation, heart failure, syncope, and even ventricular arrhythmia (VA) and sudden cardiac death (SCD). SCD is the most devastating manifestation of HCM. It mainly affects younger people and athletes, and it can happen without warning as the first symptom of HCM in asymptomatic or younger patients[5,6]. Consequently, early recognition of HCM is important. Genetic testing has improved our early recognition and diagnosis of HCM. At least 1800 mutations in more than 50 genes have now been associated with HCM pathogenesis, mutations in genes encoding sarcomere proteins being the majority[1,6,7]. With the growing implementation of next-generation sequencing, several studies have analyzed the link between gene mutations and clinical phenotypes of HCM[8,9]. However, due to the wide heterogeneity of HCM both phenotypically and genetically, the application of genotyping to guide clinical decision-making is very limited. The purpose of this review is to describe the genotype-phenotype associations of HCM by introducing the known genes related to HCM and their phenotypes.

MAIN PATHOGENIC GENES OF HCM

Among patients with HCM, 60% have an identifiable pathogenic genetic variant[10,11]. Several encode sarcomere proteins [myosin binding protein C3 (MYBPC3), myosin heavy chain 7 (MYH7), myosin light chain 2 (MYL2), MYL3, troponin T2 (TNNT2), TNNI3, tropomyosin 1 (TPM1), and actin alpha cardiac muscle 1 (ACTC1)], the two most commonly mutated being MYBPC3 and MYH7 (accounting for 50%-70% of genotype-positive patients), which encode cardiac myosin-binding protein C (cMyBP-C) and β-myosin heavy chain (β-MyHC), respectively. Other genes, such as those encoding Z-disk structural proteins [actinin α2 (ACTN2), ankyrin repeat domain 1, cysteine and glycine-rich protein 3 (CSRP3), LIM domain binding 3, myozenin 2, myopalladin, nexilin F-actin binding protein, titin-cap, vinculin, four and a half LIM domains 1 (FHL1)] or calcium regulation-related proteins [Junctophilin 2 (JPH2), phospholamban, calreticulin 3], are responsible for a small proportion of patients (1% to 5%) (Figure 1)[2,12-15]. Furthermore, only 5%-10% of HCM cases are caused infrequently by other hereditary or nonhereditary diseases, including inborn errors of metabolism (such as glycogen storage disease, carnitine disorders, and lysosomal storage diseases), neuromuscular diseases (such as Friedreich’s ataxia), mitochondrial diseases (such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), malformation syndrome (such as Noonan syndrome), and amyloidosis (such as familial amyloid transthyretin), while 25% to 30% of HCM cases are unknown cardiac hypertrophy[10]. Our laboratory conducted genetic testing on 183 out of 217 Chinese Han patients with HCM, and the results showed that 36.6% (67/183) of patients carried pathogenic alleles, with MYBPC3 and MYH7 mutations accounting for the largest proportions, 35.8% (24/67) and 31.3% (21/67), respectively, which is consistent with previous literature[16].

Figure 1 The molecular structure of sarcomeres. The molecular structure of sarcomeres in the pathogenesis of hypertrophic cardiomyopathy shows the location of genes encoding the main proteins involved in the pathogenesis of thick and thin muscle filaments. Citation: Naghi JJ, Siegel RJ. Medical management of hypertrophic cardiomyopathy. Rev Cardiovasc Med 2010; 11: 202-217. Copyright © The Author(s) 2010. Published by IMR Press[32].

MYBPC3 mutations

MYBPC3 contains more than 21 kbp in 35 exons. CMyBP-C, encoded by MYBPC3, is an important structural protein component of the sarcomere, and it participates in sarcomere assembly, stabilizes sarcomere structure, and regulates the contraction and relaxation of cardiac muscle through phosphorylation. MYBPC3 mutations contribute to 50% of HCM, and more than 350 individuals have been identified in MYBPC3, making it the most frequently mutated gene in HCM. Heterozygous truncation mutations in MYBPC3 are the principal cause of HCM[17-19]. Sixty percent of the known MYBPC3 mutations associated with HCM are heterozygous truncation mutations, which include nonsense mutations, insertions or deletions, and splicing mutations[19-21]. The main molecular pathogenic mechanism for heterozygous truncating mutations is haploinsufficiency[22]. Haploinsufficiency is caused by nonsense-mediated mRNA decay and/or the ubiquitin-proteasome system[23,24]. These mutations lead to a premature termination codon in the transcribed mRNA and are expected to produce C-terminal truncated cMyBP-C that lacks the necessary myosin-binding and/or titin-binding domains, which results in a reduction in cMyBP-C content that enhances maximal thin myofilament sliding velocities in the thick myofilament C-zone[13,17,19]. The decreased content or complete absence of cMyBP-C leads to enhanced Ca²⁺ sensitivity of myofilaments, which leads to increased combination of cardiac troponin and Ca²⁺ and thus abnormal myocardial contraction[25,26], but its mechanism has not been fully clarified.

MYH7 mutations

The MYH7 gene contains 40 exons spread over 220 kDa of genomic DNA. The MYH7 gene encodes β-MyHC, which is the predominant myosin heavy chain isoform in human cardiomyocytes. Unlike MYBPC3 with its heterozygous truncation mutations, MYH7 mainly suffers missense mutations[26]. Most of the mutations in β-MyHC cluster in functionally significant regions of myosin S1 and S2[27-29]. The molecular pathogenesis by which MYH7 mutation causes HCM is more complex and still unclear. The currently most recognized mechanisms involve Ca²⁺ homeostasis, myocardial fibrosis, and energy dysregulation[30,31].

THE CLINICAL MANIFESTATION OF HCM

The phenotypic characteristics of HCM patients are diverse. Left ventricular hypertrophy can occur in the free wall of the ventricle, apex, and papillary muscles and can be symmetrical or asymmetrical, and it can have a concentric or free-wall distribution[32]. In histopathology, the cardiac myocytes of HCM are usually hypertrophic, with disarray of myocardial fibers and myocardial fibrosis. Patients with HCM may present with chest pain, dyspnea, palpitations, angina, syncope, and even VA and SCD. SCD is the most devastating manifestation of HCM and mainly affects younger people and athletes. Importantly, many patients with HCM are asymptomatic and often identified incidentally through physical examination. SCD can be the first symptom of HCM occurring in asymptomatic or young patients without any warning. Therefore, analyzing the correlations between the pathogenic genes and phenotypes of HCM will help to identify HCM patients early and improve their prognosis.

PATHOGENIC GENES AND CLINICAL PROGNOSIS OF HCM

Genes encoding sarcomere thick or thin filament proteins

The pathogenic variants of HCM mostly occur in genes encoding sarcomere thick and thin filament proteins. Thick filament gene mutations (e.g., MYBPC3, MYH7, MYL2, MYL3, MYH6, etc.) cause HCM of the interventricular septum, while mutations in thin filament genes (e.g., TNNT2, TNNI3, TPM1, and ACTC1) commonly lead to apical HCM and centripetal HCM[33]. A meta-analysis of 7675 HCM individuals by Sedaghat-Hamedani et al[34] observed that patients with sarcomeric mutations are more susceptible to SCD and that mutations in thick filament genes lead to a more severe myocardial hypertrophy phenotype and obstruction than in patients without these mutations. Compared to thick-filament mutations, thin-filament mutations are associated with an increased likelihood of advanced left ventricular dysfunction and heart failure[35].

Among the thick filament genes, MYBPC3 and MYH7 have the most prevalent pathogenic gene mutations. It is now widely believed that MYH7 is more malignant than MYBPC3. The pathogenic mutations of the MYH7 gene are characterized by earlier onset age, larger left ventricular hypertrophy, more severe ventricular systolic and diastolic dysfunction, and a higher risk of complications such as conduction block, atrial fibrillation, VA, and SCD[6,9,36]. MYH7 mutations generally lead to end-stage heart failure with a poor prognosis. We detected three mutations in the MYH7 gene, namely, c.G1346T/p.T449N, c.C1357T/p.R453C and c.5156A>G/p.Q1719R, in three HCM families that exhibited both bradycardia and the dilated-phase HCM (DPHCM) phenotype, which is characterized by gradual left ventricular dilation and left ventricular systolic dysfunction, with an adverse outcome and a higher risk of SCD. Ours was the first report that HCM patients with an MYH7 mutation (c.G1346T/p.T449N) may develop DPHCM and suffer from cardiac block in middle age and beyond (data not published).

By comparison, patients carrying MYBPC3 mutations usually have a delayed disease onset and a milder degree of cardiac hypertrophy with favorable disease progression[37]. Although the prognosis of MYBPC3 mutation is better than that of MYH7 mutation, when MYBPC3 mutation is combined with angiotensin-converting enzyme gene mutation, the phenotype worsens[38]. Patients with the D/D genotype of the angiotensin-converting enzyme gene in the presence of HCM have an increased risk of SCD and an increased severity of hypertrophy[39]. There are relatively few reports on MYL2 and MYL3 mutations. Mutations in the MYL2 gene have been found in fewer than 5% of cases of HCM[40]. According to existing case reports, MYL2 mutations are associated with severe cardiac hypertrophy and SCD[41]. Osborn et al[42] demonstrated that MYL3 loss-of-function mutations can cause cardiomyopathy and SCD. MYH6 encodes the alpha heavy chain subunit of cardiac myosin, mutations in which cause familial HCM, left ventricular dysfunction, and heart failure exacerbation[43]. A new report by Suzuki et al[44] found that the pathogenic MYH6 variant p.Lys364fs might contribute to DPHCM. TNNT2 mutations are the most frequently observed pathogenic thin filament gene variants. TNNT2 gene mutations can manifest as mild left ventricular wall thickness with low penetrance, but they have been associated with a higher incidence of SCD and poor prognosis[6]. The TNNI3 gene encodes a subtype of troponin I and is only expressed in the myocardium. TNNI3 can lead to malignant HCM characterized by a remarkably high rate of early onset SCD[45]. The TPM1 gene accounts for 16% of all variants of thin filament proteins and is not clinically more common[46]. These have higher penetrance, causing a severe disease phenotype and unfavorable prognosis in Vietnamese patients with HCM[47]. The ACTC1 encodes a major component of thin filaments in mature cardiac myocytes and is essential for normal cardiac morphogenesis and muscle contraction. Yang et al[48] found that the ACTC1 D26N amino acid variant had an extremely high penetrance and led to diverse phenotypes. The results are summarized in Table 1.

Table 1 Pathogenic characteristics of genes associated with common sarcomere mutations in hypertrophic cardiomyopathy.

Gene	Frequency, %	Change of amino acid	Phenotype	Prognosis
MYBPC3	50	p.Glu542Gln	A delayed disease onset and a milder degree of cardiac hypertrophy	Relatively good
		p.Cys719Arg
		p.Glu334Lys
		p.Pro108lafs*9
		p.Gly1093Cys
		p.Arg668His
		p.Arg502Trp
		p.F305Pfs*27
		P.Lys1209Serfs*28
		c.2737+1(IVS26)G>T
MYH7	30-35	p.Arg453Cys	An earlier onset age, larger left ventricular hypertrophy, more severe ventricular systolic and diastolic dysfunction, and a higher risk of complications such as conduction block, atrial fibrillation, VA, end-stage heart failure and SCD	Poor
		p.Arg1045Leu
		p.Arg 719Trp
		p.Asn 391Thr
		p.Gly716Arg
		p.Arg403Gln
		p.Arg453Cys
		p.Glu848Gly
		p.Asn391Thr
		p.Thr446Pro
		p.Phe468Leu
MYL2	< 5	R58Q	Severe cardiac hypertrophy and SCD	Poor
MYL3	< 5	c.170C>A	Leading SCD	Poor
		c. 106G>T
		c.482-1G>A
MYH6	Not in detail	p.Lys364fs	Causing familial HCM, left ventricular dysfunction, and heart failure exacerbation	Poor
TNNT2	10	R92Q	Mild left ventricular wall thickness with low penetrance, a higher incidence of SCD	Poor
TNNI3	8	p.Arg21Cys	Leading to malignant HCM characterized by a remarkably high rate of early onset SCD	Poor

MYBPC3: Myosin binding protein C3; MYH: Myosin heavy chain; VA: Ventricular arrhythmia; SCD: Sudden cardiac death; MYL: Myosin light chain; HCM: Hypertrophic cardiomyopathy; TNN: Troponin.

Genes encoding Z-disk structural proteins and calcium regulation-related proteins

In addition to the thick and thin filament protein genes, genes encoding Z-disk structural proteins (e.g., ACTN2, ankyrin repeat domain 1, CSRP3, and FHL1) also regulate the phenotype of HCM. ACTN2 is expressed in cardiac muscle. Mutations of this protein have been implicated in a mild to moderate HCM and may be benign[49,50]. CSRP3 encodes muscle LIM protein, which is mainly expressed in striated muscle tissues. Heterozygous mutations of CSRP3 have been associated with mild late-onset HCM and had an apparently better prognosis, while homozygous individuals with missense mutations in CSRP3 had a more severe phenotype[49,51,52]. FHL1 is involved in sarcomere formation. Giucă et al[53] reported that FHL1 mutation leads to an elevated risk for arrhythmia and SCD and recommended that patients with HCM carrying FHL1 mutations have an implantable cardioverter defibrillator installed in advance. Other genes encoding calcium regulation-related proteins (e.g., JPH2, phospholamban, and calreticulin 3) also have an effect on the phenotype of HCM. JPH2 is the major structural protein in cardiomyocytes and is also a component of junctional membrane complexes. Mutations in the JPH2 gene are associated with HCM, and downregulation of this gene can induce heart failure, suggesting that targeting JPH2 might be an attractive therapeutic approach for pathological cardiac remodeling[54,55].

Compound genetic mutations

Patients with more than one HCM-related mutation often develop a more severe phenotype[56-58] and worse prognosis than patients with only one. Fourteen percent of childhood-onset HCM is caused by compound genetic mutations[59]. This indicates that a gene dosage effect may be responsible for early onset. Significant clinical heterogeneity remains because of different combinations of mutations. Zhang et al[60] analyzed a Chinese HCM pedigree with compound mutations and demonstrated that the combination of Met822Thr and Arg1420Trp in MYH7 was causal but relatively benign.

CONCLUSION

Collectively, HCM is a widespread inherited disease with a highly variable clinical phenotype. As sequencing technology advances, the pathogenic gene mutation spectrum and phenotypic characteristics of HCM are gradually becoming clearer. However, the precise mechanisms linking known pathogenic gene mutations and the clinical course of this heterogeneous condition remain elusive. Its onset and development are influenced by multiple factors, leading to phenotypic heterogeneity. Genetic background can only play a reference role in the diagnosis and treatment of HCM. Many studies are needed to make genetically guided clinical decision-making a reality. This paper provides a detailed reference on the pathogenic genes of HCM and their phenotypic prognosis.