MYH7 mutation in a pedigree with familial dilated hypertrophic cardiomyopathy: A case report and review of literature

Abstract

BACKGROUND

Hypertrophic cardiomyopathy (HCM) is one of the most prevalent inherited myocardial disorders and is characterized by considerable genetic and phenotypic heterogeneity. A subset of patients with HCM progress to a dilated phase of HCM (DPHCM), which is associated with a poor prognosis; however, the underlying pathogenesis remains inadequately understood.

CASE SUMMARY

In this study, we present a case involving a pedigree with familial DPHCM and conduct a retrospective review of patients with DPHCM with identified gene mutations. Through panel sequencing targeting the coding regions of 312 genes associated with inherited cardiomyopathy, a heterozygous missense mutation (c.746G>A, p.Arg249Glu) in the MYH7 gene was identified in the proband (III-5). Sanger sequencing subsequently confirmed this pathogenic mutation in three additional family members (II-4, III-4, and IV-3). A total of 26 well-documented patients with DPHCM were identified in the literature. Patients with DPHCM are commonly middle-aged and male. The mean age of patients with DPHCM was 53.43 ± 12.79 years. Heart failure, dyspnoea, and atrial fibrillation were the most prevalent symptoms observed, accompanied by an average left ventricular end-diastolic size of 58.62 mm.

CONCLUSION

Our findings corroborate the pathogenicity of the MYH7 (c.746G>A, p.Arg249Glu) mutation for DPHCM and suggest that the Arg249Gln mutation may be responsible for high mortality.

Key Words: Dilated phase of hypertrophic cardiomyopathy; Pedigree; MYH7 gene; Missense mutation; Literature review; Case report

Core Tip: A subset of patients with hypertrophic cardiomyopathy (HCM) progress to a dilated phase of HCM (DPHCM), which is associated with a poor prognosis. Our findings corroborate the pathogenicity of the MYH7 (c.746G>A, p.Arg249Glu) mutation for DPHCM, and we hypothesize that the Arg249Gln mutation in the MYH7 gene may be responsible for the high mortality of DPHCM.

INTRODUCTION

The incidence of hypertrophic cardiomyopathy (HCM) varies widely around the world, ranging from 0.02% to 0.2% in Western countries and Asian countries[1]. HCM is a primary myocardial disease characterized by left ventricle (LV) and asymmetric septal hypertrophy[2]. In most patients with HCM, the systolic function is normal, and most patients are asymptomatic for a long period of time[3]. However, a subset of patients with HCM may experience a lifelong process of left ventricular remodelling and progressive dysfunction. This stage, referred to as the dilated phase of HCM (DPHCM), has been associated with a poor prognosis[4,5]. Currently, due to unknown disease mechanisms, the clinical remedies for HCM and DPHCM are limited and serve to relieve symptoms. HCM is caused by mutations in sarcomere genes, with MYH7, which encodes the β myosin heavy chain, being one of the most common pathogenic genes. Approximately 40% of patients with HCM exhibit mutations in the MYH7 gene[6].

CASE PRESENTATION

Chief complaints

The patient (III-5) was a 31-year-old female with more than a 26-year history of fatigue after physical activity.

History of present illness

She was diagnosed with HCM at the age of 26 in 2018. Patient complained of more than a 26-year history of fatigue after physical activity. At that time, a general physical examination revealed no abnormalities and no evidence of cardiac dysfunction.

Personal and family history

There is a family history of HCM and sudden death (Figure 1). The patient’s grandfather (I-1) and aunt (II-1) died suddenly at the ages of 18 and 40, respectively. The patient reported that another aunt (II-3) was definitively diagnosed with DPHCM by a local hospital and suffered from SCD at the age of 50. The patient’s youngest aunt (II-4) was also diagnosed with DPHCM and presented with symptoms of fatigue after activity and occasional oedema in her lower extremities. Laboratory data revealed elevated levels of high-sensitivity troponin I (hsTnI) (15.8 ng/L), creatine kinase MB (5.78 ng/L), and B-type natriuretic peptide (BNP) (462.5 pg/mL). Electrocardiographic findings included a widened P wave in the limb leads and an increased P wave terminal force in lead V1. Echocardiographic assessment revealed a markedly enlarged left atrium (45 mm), thickened ventricular septum (14 mm), and significantly reduced left ventricular ejection fraction (LVEF) (45%). The proband's father (II-6) suffered from DPHCM characterized by fatigue and dyspnoea, along with dilation in the LV diameter (71 mm) and a decreased LVEF (38%). He died out of the hospital at the age of 43 with a diagnosis of cardiac dysfunction. The patient’s 9-year-old cousin (III-4) and 8-year-old son (IV-3) currently do not exhibit any clinical symptoms and have normal electrocardiogram (ECG) results, possibly due to their young ages.

Figure 1 The pedigree chart of the family. Box: Normal male; Circle: Normal female; Darkened: Affected; Slashed: Decreased; Arrow: The proband.

Physical examination

She is an outpatient and no obvious positive signs were found during the visit.

Laboratory examinations

Laboratory tests revealed mildly elevated levels of hsTnI: 75.8 ng/L and BNP: 209.4 pg/mL).

Imaging examinations

The ECG indicated a depressed S-T segment and an inverted T wave in leads I, aVL, and V6 (Figure 2). Echocardiographic assessment revealed asymmetric thickening of the wall of the LV, with a thickened ventricular septum (21 mm), a normal LV diameter (37 mm), and a LVEF of 72% (Figure 3A). Five years later, echocardiography revealed an increase in the LV diameter from 37 mm to 43 mm accompanied by a reduction in the thickness of the ventricular septum from 21 mm to 18 mm (Figure 3B). Additionally, cardiac magnetic resonance imaging (CMR) revealed thinning at the base of the ventricular septum and the LV free wall, with a measured thickness of approximately 3.4 mm at end-diastole. The LVEF decreased to 63%. Furthermore, an apical ventricular aneurysm measuring approximately 24.6 mm × 29.8 mm was observed. Late gadolinium enhancement on CMR demonstrated characteristic patchy enhancement of the ventricular septum (Figure 4).

Figure 2  The electrocardiogram of the proband showed sinus rhythm and the S-T segment of leads I, avL and V6 was depressed and the T wave was inverted change.

Figure 3 The echocardiogram. A: The first echocardiogram of the proband in 2018 was characterized by asymmetric thickening of left ventricle (LV) wall and thickening ventricular septum, without enlargement of LV (37 mm), on the horizontal long axis of LV, respectively; B: The second echocardiogram showed the enlargement of left atrium and LV (43 mm), the thinning of ventricular septum on the long axis of LV (The former is a short axis view of the papillary muscle, while the latter is a long axis view of the LV).

Figure 4 The cardiac magnetic resonance imaging findings of the proband. A: The cardiac magnetic resonance imaging (CMR) found enlargement of left atrium (shown by the blue arrow), asymmetric hypertrophy of ventricular septum (shown by the white arrows), thinning of the bottom of ventricular septal base and left ventricle free wall; B: An apical ventricular aneurysm (about 24.6 mm × 29.8 mm) was shown by CMR (the orange arrow).

FINAL DIAGNOSIS

The diagnostic criteria for DPHCM are based on previous literature reports[7,8]. DPHCM is defined as left ventricular systolic dysfunction LVEF < 50%, accompanied by one of the following conditions: (1) Left ventricular hypertrophy unexplained by other factors; (2) Left ventricular hypertrophy documented on a previous echocardiogram, unexplained by other factors; or (3) A confirmed diagnosis of familial HCM (with at least one relative having been diagnosed). Based on a family history of HCM, clinical manifestations, dynamic changes in echocardiography (Table 1), and CMR, the final diagnosis was DPHCM.

Table 1 Echocardiogram and cardiac magnetic resonance imaging characteristics of the proband, her aunt (II-4) and father (II-6).

	Proband (III-5)			Aunt (II-4)	Father (II-6)
	Echocardiogram (Figure 3A)	Echocardiogram (Figure 3B)	CMR (Figure 3C)
LA (mm)	34	38	54	45	59
LV (mm)	37	43	53	47	71
LVPW (mm)	10	10	-	8	7
IVS (mm)	21	18	21	14	10
LVEF (%)	72	64	63	45	38

LA: Left atrium; LV: Left ventricle; LVPW: Left ventricular posterior wall; IVS: Interventricular septum; CMR: Cardiac magnetic resonance imaging; LVEF: Left ventricular ejection fraction.

TREATMENT

Considering that the patient currently has no significant hemodynamic changes, beta blockers were used for treatment, and clinical observation and follow-up were conducted.

OUTCOME AND FOLLOW-UP

The patient's fatigue has improved after daily activities and requires regular outpatient follow-up.

DISCUSSION

A comprehensive literature review was conducted utilizing the PubMed and Medline databases. All English publications from January 1997 to February 2023 documenting cases of DPHCM were evaluated. A total of 35 articles were initially selected for review. Following the removal of duplicates and noncompliant cases, 22 articles containing recorded cases of DPHCM were ultimately identified for analysis[9-30]. In this study, we reviewed 26 patients diagnosed with DPHCM, as reported in 22 articles (Table 2). Among all patients diagnosed with DPHCM, the number of male patients was approximately two times greater than the number of female patients. The mean age was 53.43 ± 12.79 years, ranging from 10 to 67 years. The most common clinical manifestations included heart failure, dyspnoea, and atrial fibrillation (AF). Some patients exhibit sustained ventricular tachycardia (VT), nonsustained VT, mitral regurgitation, chest pain, or aneurysmal changes, among other symptoms. Of the 22 articles, 15 provided data regarding LV dilation size, reporting an average LV end-diastolic dimension of 58.62 mm.

Table 2 Studies included in literature review.

Ref.	Sex	Age of onset or diagnosis (year)	Size of LV (mm)	Clinical symptoms or signs	Number of cases
Morimoto et al[9]	Male	30	No available	AF, dyspnea, heart failure	1
Takemura et al[10]	Female	55	No available	Heart failure, paroxysmal AF	1
Kuno et al[11]	Male	40	54	Appetite loss, hearing loss	1
Kitahara et al[12]	Female	19	63	No obvious symptoms	1
Higashi et al[13]	Female	53	No available	Chest pain, dyspnea, and MR	1
Miyoshi et al[14]	Male	55	No available	Sustained VT, chronic AF	1
Kolekar et al[15]	Male	61	No available	Congestive heart failure, stroke, scar epilepsy, AF and VT	1
Kitamura et al[16]	Male	56	65	Congestive heart failure and sustained VT	1
Sato et al[17]	Female	27	56	Dyspnea, heart failure	1
Tanaka et al[18]	Female	53	No available	Heart failure	1
Sato et al[19]	Female	43	69.7	VT, severe heart Failure, shortness of breath and dyspnea, aneurysmal changes from the mid-septal region to the apex and NSVT	1
Canpolat et al[20]	Male	10	62	Exertional dyspnea and limited exercise capacity	1
Ueda et al[21]	Male	Mean age 67	Mean 57	Heart failure, sustained monomorphic VT	5
Fukuzawa et al[22]	Male	48	55	Dyspnea, palpitation, atrial flutter, NSVT, diastolic dysfunction	1
Matsushita et al[23]	Female	16	No available	Severe mid-ventricular obstruction	1
Ueno et al[24]	Male	57	68	Heart failure, MR	1
Matsuo et al[25]	Male	57	60	Dyspnea and NYHA functional class III heart failure	1
Benezet-Mazuecos et al[26]	Male	48	59	Congestive heart failure, LBBB	1
Kawai et al[27]	Male	38	52	AF, NSVT, premature ventricular contractions	1
Suzuki et al[28]	Male	60	44	AF, tricuspid regurgitation	1
Matsuda et al[29]	Male	47	69	Congestive heart failure	1
Akazawa et al[30]	Female	38	56	Fatigue and dyspnoea on exertion, heart failure	1

AF: Atrial fibrillation; MR: Mitral regurgitation; VT: Ventricular tachycardia; NSVT: Non-sustained VT; NYHA: New York Heart Association; LBBB: Left bundle branch block.

HCM is an autosomal-dominant cardiomyopathy. This disease is typically undiagnosed or is diagnosed at a late stage. Up to 5% of patients with HCM experience progressive myocardial remodelling and systolic dysfunction, culminating in a dramatic final stage known as the DPHCM. A recent study by Marstrand et al[5] estimated that 7.5% of individuals with HCM will progress to DPHCM within 15 years. During this phase, DPHCM demonstrates the most fundamental pathological characteristics of HCM, including myocardial cell elongation, disarray, and luminal stenosis. Research indicates that patients with DPHCM experience poor long-term survival, and AF, SCD, NYHA classification of III-IV, and an LVEF < 50% are identified as independent risk factors impacting individual survival status[31,32]. In this study, we identified a mutation in the MYH7 gene within a pedigree affected by DPHCM. This mutation is believed to contribute to the high mortality in this family.

HCM is primarily attributed to various mutated or dysregulated genes that are responsible for the synthesis of the myostatin protein in cardiac tissue. Previous research has identified more than 1400 mutations across 11 or more genes encoding proteins of the cardiac sarcomere. Among these, the most prevalent mutations are those in MYH7, MYBPC3), TNNT2, TNNI3, and TPM1[33,34]. Through panel sequencing, a mutation in the MYH7 gene, potentially responsible for HCM, was identified in this study. The MYH7 gene encodes the β-cardiac myosin heavy chain, is located on the long arm of chromosome 14, and comprises 40 exons. The Human Gene Mutation Database (http://www.hgmd.cf.ac.uk) has documented more than 350 pathogenic variants in the MYH7 gene. Mutations in the MYH7 gene are associated with a more malignant phenotype characterized by early onset, high penetrance, increased left ventricular hypertrophy, a high incidence of SCD, and poor prognosis[35,36].

Some patients with HCM develop systolic dysfunction termed DPHCM, which is associated with increased morbidity and mortality. Previous studies characterized DPHCM as an LV ejection fraction < 50% at rest (reflecting global systolic dysfunction) at study entry or during follow-up using two-dimensional echocardiography[37]. In the present study, the proband exhibited a progressive increase in LV size, a reduction in the LV ejection fraction, the formation of an LV apical aneurysm (Table 1), and a history of familial HCM, all of which are consistent with the diagnostic criteria for DPHCM. The proband's aunt and father also presented characteristics consistent with DPHCM. Furthermore, panel sequencing revealed missense mutations (c.746G>A, p.Arg249Glu) in the proband. Sanger sequencing subsequently validated this mutation in three other family members (II-4, III-4, and IV-3). Among them, the sample sequences of the two family members (III-4, IV-3) presented G/A base heterozygosity at the target mutation position of the MYH7 gene (displayed in reverse as C/T base heterozygosity) (Figure 5). A specific mutation (c.746G>A, p.Arg249Gln) in MYH7 has been documented in individuals with HCM in at least 15 studies (https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/). These studies generally suggest that the Arg249Gln mutation is a malignant missense mutation of the MYH7 gene that is characterized clinically by early onset, a family history of SCD, and poor prognosis[4,38,39]. However, there is also evidence that the Arg249Gln mutation in MYH7 does not invariably predict a poor prognosis. Posen et al[40] and Woo et al[41] reported that patients with HCM patients who have the Arg249Gln mutation did not have significantly increased LV wall thickness and had no occurrences of SCD. Furthermore, Watkins et al[38] reported that the life expectancy of patients harbouring the Arg249Gln mutation was significantly longer than that of patients with other mutations in MYH7. Our study reports a pedigree with an average onset age of 38 years and a significant incidence of SCD, with 4 out of 19 individuals affected (21%). To our knowledge, this is the first time that a mutation (c.746G>A, p.Arg249Gln) in MYH7 has been reported to cause DPHCM, which differs from previously reported phenotypes of the same mutation, possibly due to race, the incorporation of common or rare variants of other genes, and epigenetic factors.

Figure 5 Sanger sequencing DNA chromatogram in MYH7 gene of the pedigree. A: II-4; B: III-4; C: IV-3; D: II-7. Subjects (II-4, III-4 and IV-3) all presented with a heterozygous missense mutation (c.746G>A, p.R249Q). Subject II-7 was normal.

Previous studies have reported that the incidence of DPHCM ranges from 3.5% to 5.7%[4]. On average, it takes approximately 14 years from the onset of HCM to the diagnosis of DPHCM, with 66% of patients experiencing progression to death due to progressive heart failure, SCD, or required transplantation within an average period of 2.7 years[42]. Predictive factors for DPHCM include a younger age at the initial visit; a family history of HCM, DPHCM, or SCD; and greater myocardial wall thickness[4,37]. Compared with patients with DCM, those with DPHCM presented more pronounced symptoms, were more likely to be male, and presented higher incidences of prior stroke, AF, and VT/fibrillation. Furthermore, the risk of mortality was also elevated in this cohort[43,44]. Our study demonstrated that a younger age, the presence of heart failure and dyspnoea, AF, VT, chest pain, and aneurysmal changes are significantly associated with the progression of DPHCM.

CONCLUSION

Patients with HCM may progress to the dilated phase, referred to as DPHCM, which is associated with increased morbidity and mortality. However, the mechanisms underlying the transition from HCM to DPHCM remain poorly understood. In this study, we identified an MYH7 (c.746G>A, p.Arg249Glu) mutation in a pedigree with DPHCM, which may be associated with the pathogenesis and high mortality of DPHCM.