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. 2023 Mar 1;25(1):71–78. doi: 10.2478/bjmg-2022-0002

A Novel Loss-of-function Mutation in MYBPC3 Causes Familial Hypertrophic Cardiomyopathy with Extreme Intrafamilial Phenotypic Heterogeneity

Y Peng 1,2,3, J Xu 1,2,3, Y Wang 1,2,3, J Zhao 1,2,3, L Zhang 1,2,3, Z Chen 1,2,3, Y Jiang 1,2,3, S Banerjee 4, Z Zhang 1,2,3,*, M Bai 1,2,3,*
PMCID: PMC9985356  PMID: 36880031

Abstract

Cardiomyopathies are a heterogeneous group of diseases predominantly affecting the heart muscle and often lead to progressive heart failure-related disability or cardiovascular death. Hypertrophic cardiomyopathy (HCM) is a cardiac muscle disorder mostly caused by the mutations in genes encoding cardiac sarcomere. Germ-line mutations in MYBPC3 causes hypertrophic cardiomyopathy (HCM). However, most of the HCM associated MYBPC3 mutations were truncating mutations. Extreme phenotypic heterogeneity was observed among HCM patients with MYBPC3 mutations. In this study, we investigated a Chinese man who presented with HCM. Whole exome sequencing identified a novel heterozygous deletion (c.3781_3785delGAGGC) in exon 33 of the MYBPC3 in the proband. This heterozygous variant causes frameshift (p.Glu1261Thrfs*3), which predicted to form a truncated MYBPC3 protein. The proband’s father also carries this variant in a heterozygous state while the proband’s mother did not harbor this variant. Here, we report on a novel deletion in the MYBPC3 gene associated with HCM. We also highlight the importance of whole exome sequencing for molecular diagnosis for the patients with familial HCM.

Key words: familial hypertrophic cardiomyopathy, MYBPC3 gene, novel variant, heterozygous, loss-of-function.

Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder involving the heart muscle [1]. HCM is manifested with left ventricular hypertrophy (LVH) [2]. HCM is a common cardiac disorder with a world-wide incidence of 1:500 [1, 2]. Familial hypertrophic cardiomyopathy (FHC) is a rare type of HCM, manifested with myocardial hypertrophy which mostly involves the inter-ventricular septum with an autosomal dominant mode of inheritance [3, 4]. FHC is usually presented with extreme genotypic and phenotypic heterogeneity [5].

Mutations in genes encoding sarcomere proteins causes FHC [6]. Up to the date of writing, 10 candidate genes have been reported for causing FHC. In addition, more than 200 variants of these 10 candidate genes have been reported to be associated with FHC [6]. Moreover, mutations in mitochondrial DNA and PRKAG2 have also been reported to cause hypertrophic cardiomyopathy [7, 8]. Germline mutations in MYBPC3 cause 20% of all the FHC cases [6, 9].

The MYBPC3 gene encodes the Myosin-binding protein C with 1274 amino acids. Mutations in MYBPC3 is very common in HCM patients but the gene-disease association is not yet well investigated [10]. MYBPC3 associated HCM is usually presented with extreme phenotypic heterogeneity [10, 11, 12, 13]. Previous studies reported that mutations in MYBPC3 usually causes mild, moderate, or severe forms of HCM with late onset [10, 11, 12, 13, 14, 15, 16, 17]. However, HCM patients with mutations in a single gene showed late onset of disease with mild left ventricular (LV) hypertrophy and reduced chances of heart failure and cardiac death [18, 19, 20, 21, 22]. Until now, approximately 150 mutations in the MYBPC3 gene have been reported to be associated with HCM [21, 22]. Furthermore, more than 70% of the MYBPC3 mutations were frameshift mutations, resulting in formation of a C-terminal truncated protein [6, 23].

In this study, we investigated a Chinese man with familial HCM. No chromosomal abnormalities were found in the proband. A novel heterozygous deletion (c.3781_3785delGAGGC) in exon 33 of the MYBPC3 gene in the proband was identified by whole exome sequencing. This deletion causes frameshift (p.Glu1261Thrfs*3), followed by the formation of a truncated MYBPC3 protein with 1263 amino acids. The proband’s father carries this heterozygous deletion while the proband’s mother does not harbor this variant. Segregation analysis showed that this deletion is present among all the affected members as well as absent among all the unaffected members of this family and in the 100 ethnically matched healthy individuals. Our present study reported a novel mutation in the MYBPC3 gene associated with HCM and the technical importance of whole exome sequencing for identifying the mutation underlying phenotypically highly heterogenous familial hypertrophic cardiomyopathy.

Materials and methods

Ethical compliance

In this study, the Department of Cardiology of The First Hospital of Lanzhou University in Lanzhou, China enrolled a Han Chinese man with HCM (Figure 1). The ethics committee of the First Hospital of Lanzhou University, Lanzhou, China approved the study according to the recommendations of the Declaration of Helsinki. Written informed consent was obtained from the proband and all of his family members.

Figure 1.

Figure 1

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Pedigree of the described nonconsanguineous Chinese proband with HCM. Squares and circles denote males and females respectively. Individuals labelled with a slash were deceased. Roman numerals indicate generations. Arrow indicates the proband.

Clinical test details

Clinical examinations were performed for the proband for cardiovascular disorders. Electrocardiography (ECG) and Holter were used to evaluate electrophysiology status. Transthoracic echocardiography (TTE) was performed using a Phillips EPIQ7C machine (Phillips, United States). Magnetic resonance imaging (MRI) was performed using a 3.0T machine (SIMENS Skyro, Germany). The proband has a positive history of cardiac disorder in his family. The proband’s father was identified with HCM and one of his uncles died at a young age with no detailed diagnosis. Therefore, the clinical evaluation and genetic counselling for his family members was recommended.

Karyotype and chromosomal microarray analyses

G-banding karyotyping and chromosome microarray analysis (CMA) has been done to investigate the structure of the chromosome and copy number variations (CNV) [24].

Whole exome sequencing

Whole exome sequencing was performed with the proband’s genomic DNA with an Illumina HighSeq 4000. First, we use Agilent SureSelect version 6 (Agilent Technologies, United States) for capturing sequence and prepare the sequence library. Secondly, a Illumina HighSeq 4000 (Illumina, United States) was used to sequence the enriched library.

After sequencing, we aligned the reads with GRCh37. p10 by Burrows-Wheeler Aligner software. We locally aligned and recalibrated the aligned reads again by the GATK Indel Realigner and the GATK Base Recalibrator, respectively (broadinstitute.org). Next, we identified the single-nucleotide variants (SNVs) and small insertions or deletions (InDels) by using GATK Unified Genotyper (broadinstitute.org). For the last step, we annotated the identified variants with Consensus Coding Sequences Database (20130630) at the National Center for Biotechnology Information (NCBI).

Bioinformatics data analysis and interpretation

Identified variants with minor allele frequencies (MAF) less than 0.01 in the databases (dbSNP, HapMap, 1000 Genomes Project and in-house database) were selected. We classified and categorized the selected variants based on the established guideline of the American College of Medical Genetics and Genomics (ACMG) [25]. Lastly, selected variants were interpreted according to their function and association with disease with the reference of the OMIM database and previously published literature.

Sanger sequencing

Sanger sequencing was performed to validate the identified variants by whole exome sequencing.

Primer sequences are as follows; F1 5’-GCGTGCGCATCGTGGCGCTGG-3’, R1 5’-GCTGATTAGCGCTGGATCGGCG-3’. The reference sequence NM_000256.3 of MYBPC3 was used.

Analysis of Relative expression of MYBPC3 mRNA

Realtime-PCR (RT-PCR) was performed for the pro-band and his parents. RNA was extracted from whole blood sample (PrimeScript™ RT Master Mix, Takara, Japan). Primer sequences were as follows; forward primer: 5’-GCGCAGCTAGCGGCTCGGG-3’ and reverse primer: 5’- GGCGATCGGCCCGTGGCGG-3’.

Figure 2.

Figure 2

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Clinical Photos. Electrocardiogram showing signs of left ventricular hypertrophy using sokolow-lyon criteria.

In silico Analysis

The Mutation Taster (http://mutationtaster.org) was used to analyze the identified variant in the proband [26].

Results

Clinical features

In our study, the proband is a 32-year-old year old Chinese man with HCM. The proband was identified with a positive family history of cardiac disease. The proband’s father has manifested HCM and one of his uncles died at a young age with no detailed diagnosis. The patient’s complaints were episodes of palpitation that lasted a few minutes and exertional dyspnea. An electrocardiogram revealed LV hypertrophy. This was done using sokolowlyon criteria.

We performed a 24-hour Holter tape for the proband and found a normal sinus rhythm with a mean heart rate 81 bpm. We also found ventricular and supraventricular premature beats with ventricular tachycardia. Transthoracic echocardiography (TTE) was done and found left ventricular hypertrophy (LVH) with interventricular septum of 37 mm of thickness. Left ventricular ejection fraction (LVEF) was higher (73%) without any abnormalities in the regional wall motion. In addition, we found reduced systolic motion of the mitral valve as well as obstruction in the outflow tract of the LV (Figure 3. A-C). The coronary artery angiogram was normal. Magnetic resonance imaging (MRI) confirmed the echocardiographic findings (Figure 4. A-D). Late gadolinium enhancement (LGE) sequences documented mid-myocardial patchy transmural late gadolinium enhancement (LGE) in the ventricular septum.

Figure 3.

Figure 3

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Transthoracic echocardiogram of hypertrophic cardiomyopathy with left ventricular outflow tract (LVOT) obstruction. (A) Diastolic short axis view. (B) M-mode parasternal long axis view demonstrating systolic anterior motion (SAM) of the mitral valve (arrow). (C) Continuous wave Doppler through the LVOT demonstrating a peak gradient of 65 mmHg.

Figure 4.

Figure 4

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Cardiac magnetic resonance imaging of the index patient. (A) Diastolic short axis cine image shows the interventricular septal thickness is 37mm. (B) Short axis LGE image shows myocardial fibrosis. (C) Four-chamber cine image in diastolic. (D) Three-chamber cine image in systolic shows SAM.

Karyotype and chromosomal microarray analyses

We found normal chromosomal structure in the proband (46, XY). Pathogenic copy number variations (CNVs) have not been identified.

Whole exome sequencing identified a novel variant in MYBPC3

A novel heterozygous deletion (c.3781_3785delGAGGC; p.Glu1261Thrfs*3) was identified in the exon 33 of the MYBPC3 gene in the proband (Figure 5). This variant leads to a frameshift followed by the formation of a truncated MYBPC3 protein. The proband’s father also carries this variant in a heterozygous state while the proband’s mother does not harbor this variant. Segregation analysis showed that this deletion is present among all the affected members as well as absent in all the unaffected members of this family. This variant is not found in ethnically matched 100 normal control individuals.

Figure 5.

Figure 5

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Partial DNA sequences in the MYBPC3 gene by Sanger sequencing of the family. The reference sequence NM_000256.3 of MYBPC3 gene was used.

We have not found this variant in public databases (Human Gene Variant database, Online Mendelian Inheritance in Man, our in-house database of ~ 50,000 Chinese Han samples, ExAC, gnomAD, dbSNP, and 1000 Genome Database.

Relative expression of MYBPC3 mRNA

The expression level MYBPC3 mRNA in the pro-band and his father were reduced and were almost at half of the level in the proband’s mother (Figure 6). This result also indicated that the novel heterozygous deletion (c.3781_3785delGAGGC; p.Glu1261Thrfs*3) causes significant reduction of expression of MYBPC3 mRNA, and this may cause HCM in this family.

Figure 6.

Figure 6

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Relative expression of MYBPC3 mRNA.

In silico Analysis

The variant (c.3781_3785delGAGGC; p.Glu1261Thrfs*3) was predicted as a “disease causing” variant [26].

Discussion

In this study, we investigated a nonconsanguineous Han Chinese family with HCM. The proband’s father was also identified with HCM while his mother was normal. No chromosomal abnormalities were found in the proband. A novel heterozygous variant (c.3781_3785delGAGGC; p.Glu1261Thrfs*3) in the MYBPC3 gene was identified in the proband (Figure 5). This variant leads to a frameshift followed by the formation of a truncated MYBPC3 protein. The proband’s father also carries this variant in a heterozygous state while the proband’s mother does not harbor this variant. Segregation analysis showed that this heterozygous novel deletion is present among all the affected members as well as absent among all the unaffected members of this family. This variant is categorized as a “likely pathogenic” variant based on the guidelines of the American College of Medical Genetics and Genomics (ACMG) [25].

HCM is a very common disorder with extreme genotypic and phenotypic heterogeneity. Reduced penetrance and variable expressivity are often found in patients with HCM [27]. Additionally, intrafamilial phenotypic heterogeneity is also reported in HCM patients with the same genotype [27, 28]. However, most of the previous studies reported specific variations associated with the HCM phenotype in patients [29, 30]. HCM is a prevalent occurring disorder with an incidence rate of 1:500, among the general population worldwide [1, 31]. Hypertrophied and nondilated left ventricle (LV) are the main clinical symptoms for diagnosing HCM patients [32, 33]. Germline mutations in genes encoding sarcomere protein were identified in 60% of HCM patients with reduced penetrance and variable expressivity. Mutations in the MYBPC3 gene is most common among patients with inherited HCM (40%) [6, 23].

The MYBPC3 gene encodes the myosin-binding protein C of 1274 amino acids. It is a filament protein, present in cardiomyocytes. Myosin-binding protein C is involved in maintaining the structural organization of sarcomere and regulating contraction and relaxation. Previous studies reported that a majority (70%) of the germline mutations of MYBPC3 are truncating mutations [29, 30, 31]. HCM patients with truncating mutations in the MYBPC3 gene presented with severe clinical manifestations which carried the mis-sense mutations in the MYBPC3 gene [32, 33]. In comparison with HCM patients with heterozygous mutations in the MYBPC3 gene, HCM patients harboring homozygous or compound heterozygous mutations in the MYBPC3 gene were reported to have severe clinical symptoms, followed by death due to heart failure at the neonatal stage [21]. It has been reported that the differences in disease mechanism is also correlated with the type of mutations (missense or truncating mutation) of the MYBPC3 gene in heart tissues [34, 35]. Truncating mutations in the MYBPC3 gene causes haploinsufficiency while missense mutations in MYBPC3 exerts a dominant negative effect. It has also been reported that truncated myosin-binding protein C is usually degraded by nonsense-mediated RNA decay [36, 37].

HCM is, genotypically and phenotypically, an extremely heterogenous cardiac disorder. Thus, a proper clinical diagnosis is very challenging. Genetic screenings and molecular diagnoses are very helpful for the clinicians in order to provide an accurate and timely diagnosis for the patients. Due to extreme genotypic and phenotypic heterogeneity, using whole exome sequencing is more accurate and less-time consuming than single gene sequencing or targeted next generation sequencing. Whole exome sequencing is a specific, accurate and faster technique allowing the clinicians to provide accurate clinical diagnosis of the HCM patients [38, 39]. Here, we reported a novel truncating variant in the MYBPC3 gene in a family with HCM.

Acknowledgements

We are thankful to the proband and all the family members for participating in our study. This study has been funded by Natural Science Foundation of Gansu Province (20JR5RA357).

Footnotes

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Authors’ contributions

Designed the study: MB, ZZ and SB. Conducted acquisition and analysis of all the clinical data: YP, JX, YW, JZ, and LZ. WES pipelined and analyzed the data: CZ, and YJ. Selected patients and performed WES: CZ, and YJ. Supervised manuscript preparation and edited the manuscript: YP, JX, YW, ZZ, SB, and MB.

Data availability

All data used for the analyses in this report support the findings of this study are available upon reasonable request to the corresponding author.

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