云南地区一心肌病家系致病基因的筛查

The pathogenic gene screening in a cardiomyopathy pedigree of Yunnan province

目的对一扩张型心肌病和肥厚型心肌病共存的家系成员进行候选致病基因筛查，以期发现该家系的致病基因突变，并初步探讨基因型与表型的关系。方法人选2013年9月云南省第一人民医院收治的扩张型心肌病先证者及其家系成员共26名，另选取体检中心年龄、性别、种族与上述家系成员相匹配的健康云南人215名作为对照。询问先证者及其家系成员的病史、家族史，并进行体格检查、常规心电图和超声心动图检查。由华大基因公司完成先证者候选致病基因全外显子高通量测序，采用Sanger测序验证家系成员的可疑突变。通过定期门诊复查和（或）电话进行随访，内容包括家系成员死亡及其原因，是否有新发扩张型或肥厚型心肌病，随访1年或至患者死亡。结果家系中先证者（Ⅲ9）及其父亲（Ⅱ7）携带TTNc．604A〉G（P．Lys202Glu）、TAZc．580A〉G（P．Ile194Val）及MYH7c．730T〉C（p．Phe244Leu）3种错义突变，先证者起病时心功能较差，并伴有恶性心律失常，而其父无明显临床症状。健康对照人群中未发现上述突变。结论本研究发现一云南心肌病家系存在MYH7、TTN和TAZ基因突变，携带复合突变的家系成员其所患心肌病具有发病早、表型严重的特点。

Objective In this study, the sreening of candidate pathogenic gene is done among family members of an dilated cardiomyopathy（DCM） and hypertrophic cardiomyopathy （ HCM ） coexistence, and find the relationship between the genotype and the phenotype. Methods The inheritance atlas was drawn, analysis of genetic characteristics and clinical phenotype. Peripheral venous blood samples of proband and family members were candidated gene exon high-throughput sequencing sub target capture, make the result compares with related database, ultimately screening the target area of the exon and mutations of candidate genes and then using bidirectional sequencing of Sanger to sequence other family members and the health group which were matching with gender and age to testify whether there is the above mutations. Results In this family, the proband and his father carry three missense mutations, about TFNc. 604 A 〉 G（ p. Lys202Glu） ,TAZ c. 580A 〉 G（ p. Ile194Val） and MYH7c. 730 T 〉 C （ p. Phe244Leu）. The heart function of proband was failure, and accompanied malignant arrhythmia. But his father has no obvious clinical symptoms. In this family,the same genetic mutation of disease causing gene lead to different clinical phenotype, but different genetic mutation of disease causing gene lead to the same clinical phenotype. None of the mutations found in this family was found in the health group. Conclusion The patient of this family carries the genetic mutation of MYH7, TTN and TAZ. The patient of this family carries the composite mutation of MYH7 ^＋/TTN ^＋ heterozygous missense mutation and TAZ ^＋/TTN ^＋ heterozygous missense mutation may be show the performance of the genetic characteristics of early onset, severe phenotype.