Whole‑exome sequencing reveals MYH7 p.R671C mutation in three different phenotypes of familial hypertrophic cardiomyopathy

Abstract

Familial hypertrophic cardiomyopathy (HCM) is one of the most common types of genetic heart disorder and features high genetic heterogeneity. HCM is a major cause of sudden cardiac death and also an important cause of heart failure-related disability. A pedigree with suspected familial HCM was recruited for the present study to identify genetic abnormalities. HCM was confirmed by echocardiography and clinical data of the family members were collected. Genomic DNA was extracted from the peripheral blood and sequenced based on standard whole-exome sequencing (WES) protocols. Sanger sequencing was further performed to verify mutation sites and their association with HCM. WES and Sanger sequencing revealed a heterozygous missense mutation (c.2011C>T p.R671C) in myosin heavy chain 7 (MYH7) that was identified in three family members. The Arg671Cys mutation was located in exon 18 and, to the best of our knowledge, has not been previously reported in familial HCM. Furthermore, family members carrying the same mutated gene were of different sexes and clinical phenotypes. They included the proband, a 17-year-old survivor of sudden cardiac arrest with ventricular systolic dysfunction, the proband's maternal uncle, who presented with ventricular diastolic dysfunction and the proband's mother, who had no obvious clinical symptoms and did not present with cardiac dysfunction. However, echocardiology indicated that the proband's mother had an enlarged left atrium, slightly thicker right anterior wall and anterior septum and an expanded atrial septum. Therefore, HCM exhibited obvious genetic and phenotypic heterogeneity. To the best of our knowledge, the present study was the first to report such a mutation in the MYH7 gene in familial HCM. In addition, the present study demonstrated that WES is a powerful tool for identifying genetic variants in HCM.

Whole-Exome Sequencing Reveals Mutational Signature of Hypertrophic Cardiomyopathy

“…They found that although they carry the same mutant gene, different family members have different sex and clinical phenotype. 28 In this study, we found that only 4 out of 14 patients had the mutation of MYH7, which is one of the most common mutation pathogenic genes of HCM, accounting for about 20–30% of the incidence of HCM, which is consistent with the results of this study. MYH7 gene contains 40 exons, and its encoded B-MHC constitutes the main structure of myosin, which is divided into three regions: head (S1 segment), neck (S1 segment) and tail (LMM).…”

“… 13 , 27 At present, HCM is considered as a disease that is the genetic heterogeneity disease caused by the mutation of myocardial protein coding genes (usually MYH7 and MYBPC3). 15 , 28 , 29 At present, it has been reported that three members of the same HCM family have the mutation of MYH7 p.R671C. They found that although they carry the same mutant gene, different family members have different sex and clinical phenotype.…”

Proptosis secondary to bilateral extraocular muscle enlargement in Noonan syndrome with hypertrophic cardiomyopathy: A case report

“…8 More specifically, the myosin heavy chain 7 (MYH7) which is normally expressed in extraocular muscles, 9 can also be found in cardiomyocites and be responsible, if mutated, for familial hypertrophic cardiomyopathy. 10 In conclusion, this case supports the enlargement of extraocular muscles as possible cause of proptosis in Noonan syndrome. The association of extraocular muscles enlargement and hypertrophic cardiomyopathy, led us to hypothesize a common altered pathway, the MAP kinase pathway, as extraocular and cardiac muscles share a mesenchymal embryological origin.…”

“…8 More specifically, the myosin heavy chain 7 (MYH7) which is normally expressed in extraocular muscles, 9 can also be found in cardiomyocites and be responsible, if mutated, for familial hypertrophic cardiomyopathy. 10…”

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

“… Parker et al (2018) combined experimental assays and MD simulations to show that two disease mutations, A1603P and K1617Δ, in the LMM motif reduce coiled-coil helicity and lead to abnormal sarcomere assembly. Large-scale gene sequencing has additionally identified mutations in MYH6 and MYH7 that are associated with congenital heart disease ( Jin et al, 2017 ; Theis et al, 2021 ; Yu et al, 2021 ).…”