Different clinical presentation, cardiac morphology and gene mutations in two sisters with hypertrophic cardiomyopathy—A case report

Introduction

Hypertrophic cardiomyopathy (HCM) is an archetypical single‐gene disorder with an autosomal dominant pattern of inheritance. Up to date, more than 1400 polytropic sites have been identified in at least 11 genes. ¹ Due to the high heterogeneity of HCM, it is generally believed that different mutations lead to different phenotypes, and even the same genotype may have different phenotypes in different families or individuals. ² In this report, we discussed two sisters with HCM that show differences in genetic mutation and clinical phenotype.

Case report

We present the case of two siblings who share a biological relationship as sisters. The 31‐year‐old elder sister (defined as II‐1) was diagnosed with HCM 10 years ago. The diagnosis was prompted by episodes of dizziness, palpitations and post‐exercise chest tightness. The 22‐year‐old younger sister (defined as II‐2) was diagnosed with HCM 3 years ago due to atypical chest pain. They both denied any prior history of hypertension, past medical ailments or surgical procedures. It is noteworthy that during the follow‐up, II‐1 experienced a cerebral infarction, while II‐2 remained free from any complications. Of note, II‐2 received a septal myectomy 4 months ago because of left ventricular outflow tract (LVOT) obstruction. Their mother (defined as I‐1) died of heart disease (details unknown), and their father (defined as I‐1) did not show any symptoms related to HCM or any other cardiovascular diseases. A family map was presented in Figure 1.

Figure 1.

Family map of familial hypertrophic cardiomyopathy.

Significant elevations in B‐type natriuretic peptide (BNP) (elder: 865 ng/L, younger: 1081 ng/L) were identified by laboratory tests. The electrocardiogram (ECG) showed sinus rhythm in both patients. In detail, II‐1 shows ST segment depression in I, II, aVL and V4–V6 leads, and T wave inversion in I, III, aVF, aVL, V1 and V4–V6 leads (Figure 2). For II‐2, the ST segment is depressed in II, III, aVR, aVF and V4–V6 leads, and T wave inversion was found in II, III, aVR, aVF and V3–V6 leads (Figure 2).

Figure 2.

Electrocardiogram showed the non‐specific low‐down ST segment and T wave inversion in both patients.

Two‐dimensional transthoracic echocardiography (2D‐TTE) revealed an asymmetrical left ventricular (LV) myocardial hypertrophy (Maron III) in both patients. In particular, the extent of hypertrophy is more serious in II‐2, and the distribution of hypertrophic myocardium is different between II‐1 and II‐2. For II‐1, the maximal wall thickness is 18 mm at the basal level of the LV inferior wall (Figure 3A, yellow star), and the left ventricular mass index (LVMI) is 73.7 g/m². For II‐2, the maximal wall thickness is 32 mm at the anterior interventricular septum (Figure 3B, yellow star), with an LVMI of 340.5 g/m². The left atrium was enlarged in both patients (elder sister: 43 mm, younger sister: 43 mm). In addition, the right atrial (47 mm) of II‐1 was enlarged, and the pulmonary artery was found to be widened (39 mm). Furthermore, the distribution of hypertrophic myocardium in two sisters was confirmed by myocardial contrast echocardiography (MCE) (Figure 3C,D). Moreover, the typical ‘SAM’ sign can be seen only in the younger sister (Figure 3E,F). Moreover, LVOT obstruction with a pressure gradient of 50 mmHg was detected in the II‐2 by Doppler echocardiography, while the II‐1 shows no LVOT obstruction (pressure gradient = 16 mmHg). Subsequently, LV systolic and diastolic function were evaluated, and both of them present normal left ventricular ejection fraction (LVEF) (elder sister: 59%; younger sister: 69%). However, the diastolic function of the sisters is significantly compromised according to the E/A, E/e′ and left atrial volume index (LAVI) values (Table 1). Two‐dimensional strain revealed a reduced overall myocardial strain (global longitudinal strain [GLS]: elder: 8.7%, younger: 14.2%) in both subjects, especially in the hypertrophic myocardium (Figure 4). Detailed information was displayed in Table 1. The cardiovascular magnetic resonance (CMR) examination shows the same pattern as 2D‐TTE (Figure 5). Nevertheless, II‐2 received a septal myectomy 4 months ago because of LVOT obstruction and failed to undergo a CMR examination.

Figure 3.

(A, B) Representative two‐dimensional transthoracic echocardiography, (C, D) myocardial contrast echocardiography and (E, F) m‐mode echocardiography images of two sisters.

Table 1.

Echocardiographic parameters.

Item	II‐1	II‐2
MV‐E, m/s	1.13	0.99
MV‐A, m/s	0.38	0.40
E/A	2.97	2.48
MV‐E/e′	17.38	10.42
Left atrial volume, mm3	86	75
Left atrial volume index, mL/m2	56.95	48.39
LVEDd, mm	39	44
LVSDd, mm	27	27
LAD, mm	43	43
RAD, mm	47	30
PA, mm	39	25
LVEF, %	59	69
FS, %	31	39
SV, mL	39	61
CO, L/min	3.11	4.43
EDV, mL	65.91	87.69

Abbreviations: CO, cardiac output; EDV, end‐diastolic volume; FS, fraction shortening; LAD, left atrium dimension; LVEDd, left ventricular end‐diastolic dimension; LVEF, left ventricular ejection fraction; LVSDd, left ventricular end‐systolic dimension; MV‐A, mitral valve‐A velocity; MV‐E, mitral valve‐E velocity; PA, pulmonary artery; RAD, right atrium dimension; SV, stroke volume.

Figure 4.

Two‐dimensional speckle tracking imaging showed the left ventricular strain was significantly reduced.

Figure 5.

Representative cardiovascular magnetic resonance images of II‐1.

At last, peripheral venous blood was collected from the sisters and their father, and then full exome sequencing and Sanger sequencing were performed. As shown in Figure 6, the results showed that their father's genetic analysis was normal. Mutations in MYH7 (c.2302, p.G768R, G > A at the 2302 site of exon 21) and RYR2‐L4078I (c.12232, p.L4078I, C > A at the 2232 site of exon 90) were detected in both subjects (Figure 5). Strikingly, only the younger sister carried the mutation in the AKAP9 heterozygous missense gene (c.5581, p.I1861V, A > G at the 5581 site of exon 22), which led to the substitution of isoleucine at the 1861st amino acid by valine.

Figure 6.

Three detected mutations in patients. Wild‐type and mutant DNA change in sequencing (arrows).

Discussion

In our case, the two sisters both present obvious myocardial hypertrophy, compromised LV diastolic function and reduced longitudinal strain, especially in the hypertrophic myocardium. However, there are differences between the sisters. The II‐1 pattern of LV hypertrophy predominantly involves the basal level of the LV inferior wall, while the II‐2 pattern involves mainly the inferior ventricular septum and causes LVOT obstruction, which is associated with more severe heart failure. ³ , ⁴ , ⁵ Moreover, the magnitude of LV hypertrophy as well as LVMI is greater in the II‐2. In addition, the BNP level, which is positively correlated with the severity of heart failure, is higher in the II‐2. Based on the above information, one might assume that the II‐2 must present more obvious and severe clinical manifestations. Nevertheless, the facts are totally on the contrary and push us forward to further investigate their causal genes.

After thorough examination, mutations in MYH7 and RYR2 were identified in both subjects. It has been well elucidated that MYH7 is the most common (15%–25%) causal gene of familial HCM, ⁶ , ⁷ and we consider that mutations in MYH7 are the leading cause in these two patients. Mutations in RYR2 were also proven to be closely related to HCM and lead to lethal arrhythmia by causing aberrant Ca²⁺ release. ⁸ , ⁹ However, no sign of arrhythmia was discovered in these two patients. Notably, a missense variant of the AKAP9 gene was discovered only in the younger sister. AKAP9, known as a genetic modifier of congenital long QT syndrome, was proved associated with HCM for the first time and may act as a disease severity modifier. ¹⁰ However, the ECG of the younger sister showed a QT interval of 440 ms, which did not conform to the performance of long QT syndrome.

Several studies on genotype–phenotype correlation have revealed that different mutations are the reason why HCM patients manifest different severity and prognosis. ¹¹ Although the morphological, histological and clinical phenotypes of HCM are the consequence of complex interactions among a large number of determinants, ranging from the causal genetic mutation to environmental factors, the causal mutation is still considered the prerequisite and a major determinant of the phenotype. ² In the present case, the two sisters grew up in the same environment, so the environmental factors could be ignored, leaving us with the only explanation that mutation in AKAP9 is the causal factor behind the difference in phenotype. Previous studies have reported two typical cases: Maron et al. ¹² described a middle‐aged male identical twin with HCM, and both of them carry a missense variant of the CRYAB gene. The concordance of phenotype and clinical course between the two patients is remarkable, including the timing of the onset and progression of heart failure due to LVOT obstruction. Conversely, Wang et al. ¹³ reported a pair of monozygotic twins with HCM carrying the same pathogenic mutation of MYH7 (p.G768R; c.2302G > A), which, like our case, showed different clinical presentation and tissue characteristics. Nevertheless, Wang et al. did not test for other gene mutations like we did, which suggests the likely impact of epigenetics and environmental factors on the HCM phenotype.

Several studies suggest that the presence of multiple mutations is associated with more severe hypertrophy in HCM, ¹⁴ and this view of point explicates why the magnitude of LV hypertrophy as well as LVMI is greater in the younger sister, indicating that AKAP9 solidly acts as a disease severity modifier in this case, yet clinical manifestation of the sisters is confusing and lacks reasonable explanation because of the limited knowledge about the AKAP9 mutation itself. Long‐term follow‐up is required to observe the disease progression of the two sisters, and its effects should be analysed in functional studies and/or segregation in families. Another thing we notice through the 2 month follow‐up is that despite the risk factor for arrhythmia they carry, two patients did not show any signs of atrial fibrillation, ventricular tachycardia or any malignant arrhythmia. However, mutations in RYR2 and AKAP9 might herald a poor prognosis, and we will continue our follow‐up for the two sisters.

In conclusion, the present case report highlights the fact that sisters sharing the same genetic backgrounds and environmental factors might carry different gene mutations, and clinicians should be aware that a subset of patients with HCM carries ≥2 mutations, especially when family members possess different HCM phenotypes. Multiple genes should be examined instead of one. Additionally, we deduce that AKAP9 is potentially relevant to the pathogenesis of HCM. More efforts are needed in order to understand the associated risk profile between AKAP9 and HCM. Moreover, our case report assumed that echocardiography may enhance the precision and efficiency of genetic counselling and testing in HCM.

Conflict of interest statement

The authors declare no conflict of interest.

Tayier, B. , Lv, J. , Ma, L. , Guan, L. , and Mu, Y. (2024) Different clinical presentation, cardiac morphology and gene mutations in two sisters with hypertrophic cardiomyopathy—A case report. ESC Heart Failure, 11: 2432–2437. 10.1002/ehf2.14844.

Data availability statement

Data are available on request due to privacy or ethical restrictions.