一个PROC基因变异所致的遗传性蛋白C缺陷症家系的分析  

Analysis of PROC gene variant in a Chinese pedigree affected with hereditary protein C deficiency

作　　者：陈源 石佳旻 黄小夏[1] 盛安群 卢朝升[1] 朱棉棉 王楸[1] 王明山[2] 王丹[1] Chen Yuan;Shi Jiamin;Huang Xiaoxia;Sheng Anqun;Lu Chaosheng;Zhu Mianmian;Wang Qiu;Wan Mingshang;Wang Dan(Department of Pediatrics,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325000,China;Department of Medical Laboratory Center,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325000,China)

机构地区：[1]温州医科大学附属第一医院儿科,浙江325000 [2]温州医科大学附属第一医院医学检验中心,浙江325000

出　　处：《中华医学遗传学杂志》2022年第11期1233-1237,共5页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(81701485);浙江省医学会科研项目(2020ZYC-B23);温州市科技项目(2020Y0419)。

摘　　要：目的对一个遗传性蛋白C(protein C,PC)缺陷症家系进行致病变异分析,探讨其分子发病机制。方法对先证者及其家系成员采用发色底物法检测血浆蛋白C活性(protein C activity,PC:A),酶联免疫吸附法检测蛋白C抗原(protein C antigen,PC:Ag)含量。对先证者进行全外显子组测序分析,对候选变异进行Sanger测序验证;对家系中的其他成员进行相关位点的变异检测。结果先证者PC:A和PC:Ag分别降至15%和11%,其父母和姐姐的PC:A和PC:Ag也降至正常参考值的50%左右。基因分析显示,先证者PROC基因第7外显子存在c.572_574delAGA(p.Glu191_Lys192delinsGlu)杂合缺失变异,第8外显子存在c.752C>T(p.Ala251Val)杂合错义变异;其父亲存在p.Glu191_Lys192delinsGlu杂合变异,其母亲和姐姐存在p.Ala251Val杂合变异。根据美国医学遗传学与基因组学学会指南,c.572_574 del AGA(p.Glu191_Lys192 delinsGlu)判定为可能致病(PS1+PM4+PP3),c.752 C>T(p.Ala251Val)亦为可能致病(PS1+PM1+PP3)。结论先证者PROC基因第7外显子c.572_574delAGA(p.Glu191_Lys192delinsGlu)杂合缺失变异和第8外显子c.752C>T(p.Ala251Val)杂合错义变异可能是该家系的遗传学病因。上述发现丰富了PROC基因的致病变异谱,为该家系的遗传咨询提供了依据。Objective To explore the molecular pathogenesis of a Chinese pedigree affected with inherited protein C(PC)deficiency.Methods The protein C activity(PC:A)and protein C antigen(PC:Ag)of the proband and his family members were determined by a chromogenic substrate method and enzyme-linked immunosorbent assay,respectively.The proband was subjected to whole exome sequencing.Candidate variants were verified by Sanger sequencing of other members of the pedigree.Results The PC:A and PC:Ag of proband were reduced to 15%and 11%,respectively.The above parameters of his parents and elder sister were also decreased to approximately 50%of reference values.Next generation sequencing has revealed that the proband has harbored a heterozygous c.572_574delAGA(p.Glu191_Lys192delinsGlu)variant in exon 7 and a missense c.752C>T(p.Ala251Val)variant in exon 8 of the PROC gene.His father was heterozygous for the c.572_574delAGA variant,while his mother and elder sister were heterozygous for the c.752C>T variant.According to the American College of Medical Genetics and Genomics Standards and Guidelines,the c.572_574delAGA(p.Glu191_Lys192 delinsGlu)variant was predicted to be likely pathogenic(PS1+PM4+PP3).c.752 C>T(p.Ala251Val)variant was also likely pathogenic(PS1+PM1+PP3).Conclusion The deletional variant of c.572_574delAGA(p.Glu191_Lys192delinsGlu)in exon 7 and missense variant c.752C>T(p.Ala251Val)in exon 8 of the PROC gene probably underlay the inherited protein C(PC)deficiency in this pedigree.Above finding has enriched the spectrum of PROC gene variants and provided a basis for genetic counseling for this pedigree.

关 键 词：遗传性蛋白C缺陷症 PROC基因 基因变异 

分 类 号：R596[医药卫生—内科学] R440[医药卫生—临床医学]