Novel Phenotype-Genotype Correlations of Restrictive Cardiomyopathy With Myosin-Binding Protein C (MYBPC3) Gene Mutations Tested by Next-Generation Sequencing

Abstract

Background: MYBPC3 dysfunctions have been proven to induce dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or left ventricular noncompaction; however, the genotype-phenotype correlation between MYBPC3 and restrictive cardiomyopathy (RCM) has not been established. The newly developed next-generation sequencing method is capable of broad genomic DNA sequencing with high throughput and can help explore novel correlations between genetic variants and cardiomyopathies.

Methods and results: A proband from a multigenerational family with 3 live patients and 1 unrelated patient with clinical diagnoses of RCM underwent a next-generation sequencing workflow based on a custom AmpliSeq panel, including 64 candidate pathogenic genes for cardiomyopathies, on the Ion Personal Genome Machine high-throughput sequencing benchtop instrument. The selected panel contained a total of 64 genes that were reportedly associated with inherited cardiomyopathies. All patients fulfilled strict criteria for RCM with clinical characteristics, echocardiography, and/or cardiac magnetic resonance findings. The multigenerational family with 3 adult RCM patients carried an identical nonsense MYBPC3 mutation, and the unrelated patient carried a missense mutation in the MYBPC3 gene. All of these results were confirmed by the Sanger sequencing method.

Conclusions: This study demonstrated that MYBPC3 gene mutations, revealed by next-generation sequencing, were associated with familial and sporadic RCM patients. It is suggested that the next-generation sequencing platform with a selected panel provides a highly efficient approach for molecular diagnosis of hereditary and idiopathic RCM and helps build new genotype-phenotype correlations.

Keywords: diastolic dysfunction; genotype–phenotype; restrictive cardiomyopathy.

Figure 1

Pedigree of an RCM family. Squares represent male relatives; circles represent female relatives; filled symbols indicate RCM patients; slants indicate dead members; arrow represent proband; symbol with dots represent mutation carrier without clinical manifestation, + indicates MYBPC3 Q463X mutation positive; − indicates MYBPC3 Q463 mutation negative. MYBPC3 indicates myosin-binding protein C; RCM, restrictive cardiomyopathy.

Figure 2

Echocardiography of relative III4 shows (A) significant biatrial enlargement and normal biventricular size and (B) reduced lateral mitral annulus velocity (e’) by tissue Doppler image.

Figure 3

Cardiac magnetic resonance of relative III4 shows significant (A) left atrial enlargement, normal left ventricular size, and wall thickness and (B) late enhancement of papillary muscle. LA indicates left atrium; LV, left ventricle; RV, right ventricle.

Figure 4

A, Cardiac magnetic resonance of relative III6 shows biatrial enlargement, normal biventricular size, and wall thickness. B, Apical 4-chamber view by echocardiography of patient 4.

Figure 5

Mutation in myosin-binding protein C gene for (A) relative III4 and her family (c.1387C>T, p. Q463X) and (B) patient 4 (c.1000G>A, p.E334K).