A novel Loss-of-function Mutation in MYBPC3 Causes familial hypertrophic cardiomyopathy with extreme intrafamilial phenotypic heterogeneity

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.

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.