近亲婚配分别导致遗传性激肽释放酶原和高分子量激肽原缺陷症2个家系的遗传学分析  

Analysis of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein deficiency and High molecular weight kininogen deficiency

作　　者：陈碧乐[1] 谢作听[1] 郑周[2] 陈元 陈荟琳 王明山[2] 金艳慧[2] Chen Bile;Xie Zuoting;Zheng Zhou;Chen Yuan;Chen Huilin;Wang Mingshan;Jin Yanhui(Department of Blood Transfusion,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325015,China;Center of Laboratory Medicine,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325015,China)

机构地区：[1]温州医科大学附属第一医院输血科,温州325015 [2]温州医科大学附属第一医院医学检验中心,温州325015

出　　处：《中华医学遗传学杂志》2024年第9期1066-1071,共6页Chinese Journal of Medical Genetics

摘　　要：目的探讨2个近亲婚配分别导致遗传性激肽释放酶原(PK)和高分子量激肽原(HMWK)缺陷症家系的分子致病机制。方法选取分别于2021年12月3日和2022年6月16日就诊于温州医科大学附属第一医院的1个PK缺陷症家系(共4代10人)和1个HMWK缺陷症家系(共3代6人)作为研究对象。收集相关临床资料,检测先证者及其家系成员的相关凝血指标。提取受试者外周血基因组DNA后,对KLKB1和KNG1基因进行测序,并对候选变异进行生物信息学分析。本研究通过温州医科大学附属第一医院医学伦理委员会的审查(伦理号:KY2022-R193)。结果先证者A为29岁女性,与其弟弟血浆PK活性均极度降低(<1.0%)。先证者B为66岁男性,血浆HMWK活性极度降低(<1.0%)。测序结果发现,先证者A及其弟弟KLKB1基因第5外显子均存在c.417_418insCATTCTTA(p.Arg140Hisfs*3)纯合插入变异,其祖母、外祖母、父亲、母亲、妹妹和儿子均携带杂合插入变异,其外祖父和丈夫均为野生型;先证者B的KNG1基因第4外显子存在c.460C>A(p.Pro154Thr)纯合错义变异,其儿子携带杂合错义变异,家系其他成员均为野生型。根据美国医学遗传学与基因组学学会(ACMG)相关指南,上述2个变异分别被评定为致病性(PVS1+PM2_Supporting+PM4)与可能致病性(PS4+PM2_Supporting+PP3+PP4)。结论KLKB1基因c.417_418insCATTCTTA(p.Arg140Hisfs*3)与KNG1基因c.460C>A(p.Pro154Thr)变异可能分别为2个家系PK活性与HMWK活性降低的遗传学病因。ObjectiveTo analyze the genetic variants of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein(PK)and High molecular weight kininogen(HMWK)deficiency and explore their molecular pathogenesis.MethodsA PK deficiency pedigree(10 individuals from 4 generations)and a HMWK deficiency pedigree(6 individuals from 3 generations)which were admitted to the First Affiliated Hospital of Wenzhou Medical University on December 3,2021 and June 16,2022,respectively were selected as the study subjects.Clinical data of the two pedigrees were collected,and the related coagulation indexes of the probands and their family members were determined.Genomic DNA of the two pedigrees was extracted from peripheral blood samples.This study was approved by the First Affiliated Hospital of Wenzhou Medical University(Ethics No.KY2022-R193).ResultsThe plasma PK activity of proband A,a 29-year-old female,and her brother were extremely low(<1.0%).Proband B was a 66-year-old male with extremely low plasma HMWK activity(<1.0%).Genetic sequencing revealed that the proband A and her brother had both harbored a homozygous c.417_418insCATTCTTA(p.Arg140Hisfs*3)insertional variant in exon 5 of the KLKB1 gene,with her grandmother,maternal grandmother,father,mother,sister and son all carrying heterozygous insertion variant,and her ancestor father and husband are both wild-type.Proband B had harbored a homozygous c.460C>A(p.Pro154Thr)missense variant in exon 4 of the KNG1 gene,and his son carries a heterozygous missense variant.All other members of the pedigree are wild type.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the variants were respectively rated as pathogenic(PVS1+PM2_Supporting+PM4)and likely pathogenic(PS4+PM2_Supporting+PP3+PP4).ConclusionThe c.417_418insCATTCTTA(p.Arg140Hisfs*3)variant of the KLKB1 gene and the c.460C>A(p.Pro154Thr)variant of the KNG1 gene probably underlay the decreased PK and HMWK activities in the two pedigrees,respectively.

关 键 词：激肽释放酶原缺陷症 高分子量激肽原缺陷症 KLKB1基因 KNG1基因 

分 类 号：R596[医药卫生—内科学]