PKD1基因变异致多囊肾病家系1例的临床与遗传学分析  

Clinical and genetic analysis of a family with polycystic kidney disease caused by PKD1 gene mutation

作　　者：刘庄[1] 王钦[1] 张敏[1] 魏泽锋[1] 李泽武 杨爱军[1] Liu Zhuang;Wang Qin;Zhang Min;Wei Zefeng;Li Zewu;Yang Aijun(Department of Reproductive Medicine,the Affiliated Hospital of Jining Medical University,Jining 272029,China)

机构地区：[1]济宁医学院附属医院生殖医学科,济宁272029

出　　处：《国际遗传学杂志》2024年第1期55-62,共8页International Journal of Genetics

基　　金：济宁市科技局重点研发项目(2022YXNS086、2022YXNS014);山东省自然科学基金(ZR2022MH094)

摘　　要：目的探讨1个常染色体显性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)家系PKD1基因变异的致病性,并进行遗传咨询和再生育指导。方法采集家系成员及100名健康对照者外周血,通过全外显子测序法筛选先证者全外显子组变异基因;应用PCR及Sanger测序验证先证者及其家系成员候选变异基因位点,并进一步筛查健康对照者;结合先证者家系的临床信息及ACMG/AMP指南进行新变异的致病性解读,应用ExAC、dbSNP、HGMD、千人基因组、ClinVar、PKDB、Mutation Taster和Uniprot数据库及软件进行突变人群频率和生物信息学分析。结果超声检查显示先证者双肾多发囊性回声;全外显子测序结果显示先证者及其女儿、父亲、姑姑、姑表妹均存在PKD1 c.4076T>C(p.Leu1359Pro)杂合错义变异,且100名健康对照者中均未发现该变异。本家系中的多囊肾患者存在PKD1 c.4076T>C(p.Leu1359Pro)杂合错义变异,根据ACMG/AMP指南,该变异分类为可能致病性(PS4_Supporting+PP1_Moderate+PM2_Supporting+PP3+PP4)。结论PKD1基因c.4076T>C(p.Leu1359Pro)杂合错义变异的发现丰富了PKD1基因的变异谱,为该家系的遗传咨询和遗传学诊断提供了依据,避免了再生育发病的风险。Objective To investigate the pathogenic of PKD1 gene mutation in an autosomal dominant polycystic kidney disease(ADPKD)family,and to provide genetic counseling and reproductive guidance.Methods Peripheral blood samples were collected from family members and 100 healthy controls,and the whole exome mutation genes of the proband were screened by the whole exome sequencing.PCR and Sanger sequencing were used to verify the candidate mutation gene loci of the proband and his family members,and further screen healthy controls.Combined with the clinical information of the proband’s family and the ACMG/AMP guidelines,the pathogenic interpretation of the new mutation was performed using ExAC,dbSNP,HGMD,1000 genomes project,ClinVar,PKDB,Mutation Taster and Uniprot databases and software were used to analyze the mutation population frequency and the analysis of bioinformatics.Results Ultrasound examination showed multiple cystic echoes in both kidneys of the proband;high-throughput sequencing results showed that the proband and his daughter,father,aunt and cousin all had heterozygous missense mutation of PKD1 gene c.4076T>C(p.Leu1359Pro),and this mutation was not found in 100 healthy controls.PKD1 gene c.4076T>C(p.Leu1359Pro)heterozygous missense mutation was found in the polycystic kidney patients in this family.According to the ACMG/AMP guidelines,the mutation was classified as likely pathogenic(PS4_Supporting+PP1_Moderate+PM2_Supporting+PP3+PP4).Conclusion The discovery of heterozygous missense mutation of PKD1 gene c.4076T>C(p.Leu1359Pro)enriches the mutation spectrum of PKD1 gene,provides a basis for genetic counseling and genetic diagnosis of the family,and avoids the risk of re-fertility.

关 键 词：常染色体显性多囊肾病(ADPKD) 全外显子测序 基因 新变异 

分 类 号：R692[医药卫生—泌尿科学]