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MYH7 Gene-Related Mutation P.V878L Identified in a Chinese Family with Hypertrophic Cardiomyopathy

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MYH7 Gene-Related Mutation P.V878L Identified in a Chinese Family with Hypertrophic Cardiomyopathy EXPERIMENTAL STUDY MYH7 Gene-Related Mutation p.V878L Identified in a Chinese Family with Hypertrophic Cardiomyopathy Yuan Du, 1 MD, Ya Wang,1 MD, Xiu Han,1 MD, Zhanbin Feng,2 MD and Aiqun Ma,1,3,4 MD Summary Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiovascular diseases and possesses a high risk for sudden cardiac death. Although mutations in more than 20 genes have been reported to be associated with HCM thus far, the genetic backgrounds of most HCM patients are not fully understood. We performed a genetic analysis in a Chinese family that presented with HCM using next-generation sequenc- ing (NGS). Clinical data, family histories, and blood samples were collected from the proband and family mem- bers. Five patients showed typical clinical symptoms of HCM. One subject was the victim of sudden cardiac death. By NGS, we determined that these subjects with HCM symptoms carried a missense heterozygous ge- netic mutation c.2632C>A (p.V878L) in the myosin heavy chain 7 (MYH7) gene with an autosomal dominant pattern of inheritance. Individuals without this mutation showed no symptoms or cardiac structural abnormali- ties related to HCM. Bioinformatics evaluation predicted this mutant as “damaging” and “disease causing”. Ad- ditionally, sequence alignment showed that this mutant is located in an evolutionarily conserved region of MYH 7 in multiple species. Our results describe a potentially pathogenic mutation associated with HCM, which may extend the spectrum of HCM phenotypes related to MYH7 gene mutations. (Int Heart J 2019; 60: 1415-1420) Key words: Next generation sequencing, Bioinformatic ypertrophic cardiomyopathy (HCM) is a primary normalities in cardiomyocytes, which result in myofibrillar myocardial disease characterized by left ven- disorganization, myocyte hypertrophy, and interstitial fi- H tricular (LV) hypertrophy, accompanied by my- brosis.8) ofibrillar disarrays and diastolic dysfunction of cardiac In the above-mentioned genes, myosin heavy chain 7 ventricles, which occurs in the absence of other cardiovas- (MYH7) and myosin binding protein C3 (MYBPC3)are cular or systemic causes.1) The prevalence of HCM is the two most frequent disease-causing genes, which are 1:500 in the general population2) and about 0.16% in estimated to account for approximately half of the patients China.3) Currently, HCM appears to be the leading cause with familial HCM;9) while other genes including troponin of sudden death in young people, with particular predilec- T (TNNT2), troponin I (TNNI3), α-tropomyosin (TPM1), tion for children and young adults (age < 30 years).4) and α-actin (ACTC) each account for a small proportion HCM is the first cardiac disease associated with a of patients (1% to 5%).6) However, other genetic altera- genetic background and it is one of the most common in- tions associated with HCM are under exploration. Re- herited cardiovascular diseases.2,4) Until now, pathogenic/ cently, striking scientific advances in molecular genetics causative mutations have been identified in 25～30 have resulted in the availability of comprehensive genetic genes.5) About 90% of pathogenic mutations are missense testing and enabled us to seek out more genetic mutations mutations in which one highly conserved DNA nucleotide in families with HCM. is replaced by a different nucleotide resulting in a differ- Traditionally, genetic studies focus on the most likely ent codon, leading to alterations of the physical and func- HCM-related genes using conventional Sanger sequencing, tional properties of proteins.6) HCM is an autosomal domi- despite the practical difficulties of keeping up with the nant hereditary disease, therefore, each first-degree relative ever-increasing number of test requests and disease- of an affected patient has a 50% chance of carrying the associated genes.7) In recent years, next-generation se- mutation and potentially developing HCM.7) HCM-related quencing (NGS) has emerged as a revolutionary technol- mutations lead to sarcomeric and/or regulatory protein ab- ogy which enables the generation of a high amount of ge- From the 1Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, 2Department of Cardiovascular Medicine, Ninth Hospital of Xi’an, Xi’an, China, 3Shaanxi Key Laboratory of Molecular Cardiology, Xi’an Jiaotong University, Shaanxi, China and 4Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Shaanxi, China. This work was supported by the Key Program of International Cooperation and Exchanges of Shaanxi, China (No. 2016KW23-05 to YD). Address for correspondence: Aiqun Ma, MD, Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, Shaanxi 710061 China. E-mail: [email protected] Received for publication March 21, 2019. Revised and accepted August 22, 2019. Released in advance online on J-STAGE November 15, 2019. doi: 10.1536/ihj.19-146 All rights reserved by the International Heart Journal Association. 1415 IntHeartJ 1416 DU, ET AL November 2019 netic data.8) This massive amount of information has trig- alignment algorithm that employs a suffix array that is gered the development of potent bioinformatic tools to represented by the Burrows-Wheeler Transform (BWT). help interpret potential causality implications.9) In this re- All the mutations were compared with databases such as port, taking advantage of the NGS assay combined with dbSNP, ExAC or 1000 genome projects. All the mutations clinical assessments, we identified a MYH7 mutation found that can potentially cause HCM were subject to (c.2632C>A [p.V878L]) in a Chinese family affected by Sanger sequencing (ABI3130) for verification. HCM. This report extends the spectrum of HCM pheno- Conservation analysis and bioinformatics prediction: types associated with MYH7 gene mutations. The homologs (similarity attributable to descent from a common ancestor) of the region including Val878 in homo sapiens were detected (HomoloGene, http://www.ncbi.nlm. Methods nih.gov/homologene). The potential pathogenicity of the Clinical assessment: Informed consent was obtained from identified missense mutations was evaluated by combining all affected family members and control subjects. Detailed different methods: PolyPhen-2 (http://genetics.bwh.harvar clinical evaluation, including accurate medical history, d.edu/pph2), SIFT (http://sift.jcvi.org), and Mutation physical examination, serum creatine kinase (CK), 12-lead Taster (http://www.mutationtaster.org). The reference pro- electrocardiogram (ECG), and transthoracic echocardiogra- tein ID of MYH7 was ‘P12883’ and the Ensembl tran- phy were performed in the proband and her relatives. Due script ID was ‘ENST00000355349’. to the long distance to the hospital, several members did not present to the hospital for clinical examination. One Results hundred unrelated blood donors with normal ECGs and echocardiography served as controls. This study was ap- Clinical features of the proband: The proband of this proved by the Ethics Committee of the First Affiliated family was a 48-year-old female (III-6, Figure 1 and Ta- Hospital of Xi’an Jiaotong University (Xi’an, Shaanxi) ble). She had recurrent paroxysmal palpitations and chest and conforms to the principles outlined in the Declaration distress for about 6 months, without angina pectoris, of Helsinki. dyspnea or syncope. Physical examination revealed a Echocardiographic diagnostic criteria for HCM in- grade III/VI harsh long systolic murmur heard best over clude an unexplained maximal wall thickness (measured the left lower sternal border. An ECG revealed sinus at end-diastole) !15 mm (or > 2 standard deviation for rhythm and LV hypertrophy. There were nonspecific ST-T age, height and gender) in any myocardial segment or wave changes in the anterolateral leads and Q wave in the septal/posterior wall thickness ratio of > 1.3 in a nondi- inferior leads (Figure 2A). An echocardiogram showed lated ventricle and > 1.5 in the setting of systemic hyper- septal hypertrophy of 23 mm (Figure 2B) and a left ven- tension.10) tricle outflow tract (LVOT) gradient of 43 mmHg at rest. Samples: Blood samples were collected from the proband Cardiac catheterization revealed systolic obliteration of the and her family members. RNA-free high-molecular-weight left ventricle with hypertrophied septum further impinging DNA was prepared using a Tiangen Blood DNA Extrac- into the cavity (Figure 2C) and a pressure gradient of 31 tion Kit (TIANGEN[DP318-03(200)], China). The quality mmHg across the LVOT. Coronary angiography revealed and concentration of genomic DNA samples were as- 30% stenosis of the proximal left circumflex coronary ar- sessed by agarose gel electrophoresis and a NanoDrop tery (LCX). The left anterior descending (LAD) and right spectrophotometer. coronary artery (RCA) were normal. Next generation sequencing and analysis: For genes Pedigree analysis: During the proband’s clinical visits, from nucleus genome, 1,000 ng of genomic DNA was we were informed that her father (II-1, Figure 1) died fragmented into an average size of 250 bp, and then the suddenly at the age of 54, most likely from sudden car- fragmented genomic DNA was used to prepare sequenc- diac death (SCD), and her older brother (III-1) was diag- ing library. 8 bp barcoded sequencing adaptors were then nosed with HCM at a different hospital one year previ- ligated with the DNA fragments before final hybridization ously. Unfortunately, the records of her father were not with a customer-made gene panel focused exome of genes available to us. Her mother (II-2) had a history of hyper- related to cardiovascular disease (NimbleGen, Roche). tension for more than 20 years. An echocardiogram This NGS gene panel not only includes cardiomyopathy- showed mild enlargement of the LV and left atrium (LA) related genes, but also includes all the genes associated and slight decline of ejection fraction (EF) with no septal with cardiovascular diseases (1876 genes, detailed infor- hypertrophy. Her two uncles (II-3 and II-5), older brother mation in Supplemental Table).
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