1个结蛋白基因新突变致扩张型心肌病家系的临床特点及遗传分析  

Clinical features and genetic analysis for a family with dilated cardiomyopathy induced by a novel mutation of DES gene

作　　者：于莉 宋贵波[3] 靳冰玉 干学东[2] 邱雪平[1] 王陈[1] 程亚婷 郑芳[1] YU Li;SONG Guibo;JIN Bingyu;GAN Xuedong;QIU Xueping;WANG Chen;CHENG Yating;ZHENG Fang(Center for Gene Diagnosis&Department of Laboratory Medicine,Zhongnan Hospital of Wuhan University,Wuhan 430071,Hubei;Department of Cardiovascular Medicine,Zhongnan Hospital of Wuhan University,Wuhan 430071,Hubei;Department of Laboratory Medicine,First Affiliated Hospital of Kunming Medical University,Kunming 650032,Yunnan,China)

机构地区：[1]武汉大学中南医院基因诊断中心&检验科,武汉430071 [2]武汉大学中南医院心血管内科,武汉430071 [3]昆明医科大学第一附属医院检验科,昆明650032

出　　处：《临床检验杂志》2022年第12期929-933,共5页Chinese Journal of Clinical Laboratory Science

摘　　要：目的 对1个扩张型心肌病的家系进行遗传学分析,探讨其致病性基因变异位点,为遗传咨询提供数据支持。方法 收集该家系现存成员的临床资料和外周血,采用外周血DNA提取试剂盒提取白细胞基因组DNA,采用全外显子组二代测序技术筛选出与扩张型心肌病相关的可疑致病性变异,用Sanger测序对变异位点进行验证,结合家系共分离分析及多种生物信息学方法(如UniProt、PolyPhen-2和Mutation taster、ANTHEPROT、PyMOL等)综合验证和预测该变异的有害性,并根据ACMG指南对该变异位点进一步解读。结果 该扩张型心肌病家系符合常染色体显性遗传模式,患病成员均携带结蛋白基因(desmin,DES),是未曾报道过的一种杂合错义新突变DES c.140G>T(p.Ser47Ile)。生物信息学预测结果显示,该突变可改变蛋白质的二级结构,增加其疏水性并使其抗原性下降,还可使该位点原有的氢键和潜在的磷酸化位点丢失。根据ACMG指南可将该突变解读为可能致病的变异。结论 新发现的DES基因c.140G>T(p.Ser47Ile)变异可能是该常染色体显性遗传家系的致病原因,该家系患者出现临床表型的时间相对较早且预后不良,突变的检测有助于患者早期诊断与个性化的临床管理及治疗。Objective The aim of this study is to analyze the genetic characteristics and mutation site of a family with dilated cardiomyopathy for providing genetic counseling. Methods The clinical data and peripheral blood sample of the proband and his family members were collected. The genomic DNA of leukocytes was extracted by using DNA extraction kit. Then the whole exome sequencing was conducted by using the genomic DNA. The mutation sites of possible pathogenic gene associated with dilated cardiomyopathy were screened by whole exome second-generation sequencing. The mutation sites were verified by Sanger sequencing.Combined the family coseparation analysis with various bioinformatics methods, such as UniProt, PolyPhen-2 and Mutation taster, the harmfulness of the mutations was validated comprehensively and predicted. Finally, the pathogenicity of the mutation was evaluated in accordance with the recommendations of the American College of Medical Genetics and Genomics(ACMG). Results This family with dilated cardiomyopathy was corresponding to an autosomal dominant inheritance pattern. The results of the sequencing showed that all the patients in the family members carried a new heterozygous missense mutation of desmin(DES) gene, c.140G>T(p.Ser47Ile), which has never been reported before. The prediction software of bioinformatics suggested the mutation could affect the secondary structure, increase hydrophobicity and decrease antigenicity of the protein, lead to the loss of the hydrogen bond and the potential phosphorylation site. Based on the ACMG guidelines, this mutation can be interpreted as a category of potentially pathogenic variant. Conclusion The novel mutation of DES c.140G>T(p.Ser47Ile) may be the pathogenesis of the autosomal dominant inheritance in this family. The clinical phenotype caused by this mutation may appear relatively early with poor prognosis. The detection for the mutation should be helpful for early diagnosis and personalized treatment and management of the patients.

关 键 词：扩张型心肌病 DES基因 结蛋白 新突变 

分 类 号：R446[医药卫生—诊断学] R542.2[医药卫生—临床医学]