一个汉族肥厚型心肌病家系中MYH7-D554Y新发突变的基因型与表型研究

Analysis of genotype-phenotype correlation for a novel MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy

目的分析一个汉族肥厚型心肌病家系中MYH7-D554Y基因突变的基因型与临床表型的相关性。方法应用靶向外显子捕获测序技术检测先证者96个与遗传性心肌病相关基因，采用Sanger测序法验证可疑突变在家系成员和300位健康志愿者中的表达，在家系中进行基因型与临床表型的共分离分析。应用ClustalX软件分析突变氨基酸在物种间的保守性，应用Polyphen-2、Provean、SIFT、Mutation Taster生物信息学软件分析的突变蛋白的致病性。结果本家系共筛查一级亲属5人，经临床筛查4人确诊为肥厚型心肌病，且先证者左室室壁极度肥厚，最大厚度35mm。确诊的4人均携带杂合突变MYH7 c．1660G〉T（p．Asp554Tyr），Ⅱ2未携带此突变表型正常。在300名健康志愿者中未检测到此突变。HGMD数据库及其他突变数据库未收录此突变，为新发突变。种间保守性分析发现MYH7基因编码的第554位氨基酸在进化上高度保守，生物信息学分析预测该突变为有害突变。结论该家系中，携带MYH7-D554Y突变的成员均有肥厚型心肌病临床表型，不携带的成员表型正常，推测此突变可能是该家系的主要致病基因。

Objective To explore the genotype-phenotype correlation of a MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy. Methods Ninety six cardiovascular disease-related genes were detected in the proband by exonic amplification and high- throughput sequencing. Suspected mutations were verified by Sanger sequencing among 300 healthy controls as well as family members of the proband. The pathogenicity and conservation of the detected mutations were analyzed with ClustalX, MutationTaster, PolyPhen-2, Provean and SIFT software. Results Four of the 5 first-degree relatives of the proband were diagnosed with hypertrophic cardiomyopathy. The proband has featured extremely hypertrophic left ventricular wall with a maximal thickness of 35 mm. Genetic testing showed that four of them have carried a heterozygous e. 1660G〉T （p. Asp554Tyr） mutation of the MYH7 gene, who the remaining one was phenotypically normal and did not carry the mutation. The mutation has not been recorded by the Human Gene Mutation Database （HGMD） and other databases. Bioinformatics analysis suggested that the mutation site is highly conserved and that the mutation is pathogenic. Conclusion The p. Asp554Tyr mutation of the MYH7 gene probably underlies the hypertrophic cardiomyopathy in this pedigree.