扩张型心肌病家系罕见受磷蛋白致病基因突变

目的 对一扩张型心肌病(dilated cardiomyopathy, DCM)家系行候选致病基因全外显子高通量测序，以寻找该家系的致病基因，并分析其基因型和表型的关系。方法 收集在武汉大学人民医院就诊的一位DCM患者及其家系成员的临床资料及血液标本。与先证者及其家属签订知情同意书，绘制家谱图，由我院临床分子诊断中心对先证者进行候选致病基因全外显子高通量测序，获得可疑突变后，用Sanger测序对家系其他成员进行验证，寻找致病基因。结果 家系先证者6号染色体外显子上存在受磷蛋白(phospholamban, PLN)基因的精氨酸缺失突变c.36_38delAAG (p.Arg13del)，为该家系的可疑致病基因。先证者目前心脏扩大，心功能显著下降，且超声心动图提示左心室附壁血栓形成，心电图提示肢导低电压以及胸导联R波极度减低。先证者母亲及其大姐因心脏病死亡，二姐目前患有扩张型心肌病，其子女未检测到致病基因。受磷蛋白作为肌质网钙离子循环中的调节蛋白，它的基因表达、分布、功能与心室的收缩功能密切相关。结论 本研究发现DCM家系中存在PLN基因缺失突变：PLN c.36_38delAAG (p.Arg13del)，是家族性扩张型心肌病的重要致病基因，此突变在汉族人群中尚属首次报道。

Rare causative gene mutation in phospholamban in families with dilated cardiomyopathy

Objective To find out the pathogenic gene among family members of dilated cardiomyopathy (DCM) by high-throughput sequencing of the candidate gene exon, and analyze the relationship between the genotype and the phenotype. Methods The proband was diagnosed with dilated cardiomyopathy at Renmin Hospital of Wuhan University. The clinical data and blood specimens of the DCM proband and her family members were collected, the inheritance atlas was drawn, and analysis of genetic characteristics and clinical phenotype was performed, and the informed consent was signed with the precursor and their family members. The high-throughput sequencing of all exons of the candidate pathogenic genes was carried out by the clinical molecular diagnosis center of our hospital. And ultimately the target area of the exon and mutations of candidate genes were screened. Then bidirectional sequencing of Sanger was used to sequence other family members which were matching with gender and age to testify whether they are the above mutation. Results the deletion mutation c.36_38delAAG (p.Arg13del) of the phospholamban (PLN) gene was found on the exons of chromosome 6 in the proband of this DCM family, by comparison and analysis of the sequencing results of the DCM family and normal people, and through multiple biological database data filtering. Phospholamban, as a regulatory protein in the cycling of calcium in the sarcoplasmic reticulum, its gene expression, distribution and function is closely related to heart function. Conclusion the whole genome exon sequencing was used to detect the pathogenic gene and mutation site in a DCM family: PLN c.36_38delAAG (p.Arg13del). The mutation of phospholamban gene caused the heart enlargement and abnormal cardiac function of the DCM patient, which is an important pathogenic gene of familial dilated cardiomyopathy. This mutation is the first report in the Han population.