两个Alport综合征家系的分子诊断及胚胎植入前遗传学诊断  

Molecular diagnosis and preimplantation genetic diagnosis of two Alport syndrome pedigrees

作　　者：张在卉 范仲蠡 黄秋香 毛丽华 卢克友[1] 王志红 ZHANG Zaihui;FAN Zhongli;HUANG Qiuxiang;MAO Lihua;LU Keyou;WANG Zhihong(Central Laboratory,Fuqing City Hospital Affiliated to Fujian Medical University(Fuqing City Hospital of Fujian),Fuzhou,Fujian 350300,China;Center for Medical Genetics,Laboratory of Basic Medicine,Fuzong Clinical College of Fujian Medical University(900th Hospital of the Chinese People’s Liberation Army Joint Logistics Support Force),Fuzhou,Fujian 350025,China;Department of Obstetrics&Gynecology,Fuzong Clinical College of Fujian Medical University(900th Hospital of the Chinese People’s Liberation Army Joint Logistics Support Force),Fuzhou,Fujian 350025,China)

机构地区：[1]福建医科大学附属福清市医院(福清市医院)中心实验室,福建福州350300 [2]福建医科大学福总临床医学院(中国人民解放军联勤保障部队第九〇〇医院)基础医学实验室医学遗传中心,福建福州350025 [3]福建医科大学福总临床医学院(中国人民解放军联勤保障部队第九〇〇医院)妇产科生殖中心,福建福州350025

出　　处：《中国优生与遗传杂志》2024年第12期2603-2607,共5页Chinese Journal of Birth Health & Heredity

基　　金：福建省自然科学基金(2023J011341)。

摘　　要：目的分析2个Alport综合征家系的临床特征,明确家系先证者及其他家系成员的分子诊断,提供遗传咨询、产前诊断及胚胎植入前遗传学诊断(PGD),预防Alport综合征患儿出生。方法收集2例Alport综合征家系的临床资料,采集先证者及核心家系成员的外周血,提取基因组DNA行全外显子组测序(WES),对候选变异进行生物信息学分析,并对先证者行Sanger测序验证及家系成员变异分析。在明确致病基因变异的基础上,对家系1的高危胎儿行产前诊断;对家系2,运用联合诊断单基因病和染色体病非整倍体高通量测序与连锁分析(MARSALA)策略行PGD。结果先证者1存在COL4A5基因c.3703G>T(p.Gly1235Cys)半合子变异,遗传自其母亲,ACMG致病性评级为可能致病性变异(PM1+PM2_Supporting+PM6+PP3),该变异已被ClinVar数据库收录。先证者2存在COL4A5基因c.4913G>A(p.Cys1638Tyr)杂合变异,遗传自其母亲,该变异已报道并收录为可能致病。家系1产前诊断结果提示胎儿为女性,存在与其母亲相同的杂合变异。家系2经遗传咨询选择PGD生育后代,MARSALA检测并移植1枚无特定基因异常、染色体整倍体的胚胎后成功妊娠,产前诊断结果与PGD结果一致。结论本研究通过基因检测明确了2个Alport综合征家系的分子病因,对这2个家系分别进行了产前诊断和PGD,家系2成功生育健康后代。PGD是Alport综合征家系生育健康后代的有效方法。Objective To analyze the clinical features of two families with Alport syndrome and identify the molecular diagnosis of the family proband and other family members,provide genetic counseling,prenatal diagnosis and preimplantation genetic diagnosis(PGD)to prevent the birth of the children with Alport syndrome.Methods Clinical data of two families with Alport syndrome were collected,peripheral blood was collected from the proband and nuclear family members,genomic DNA was extracted for whole exome sequencing(WES),and candidate variants were analyzed bioinformatically,followed by Sanger sequencing validation in the proband and variant analysis in the family members.Based on the identified pathogenic gene variants,prenatal diagnosis was performed on high-risk fetus in pedigree 1,and PGD was performed by a strategy of mutated allele revealed by sequencing with aneuploidy and linkage analyses(MARSALA)in pedigree 2.Results WES and Sanger sequencing results revealed that the proband 1 had the c.3703G>T(p.Gly1235Cys)hemizygous variant in the COL4A5 gene,which was inherited from his mother,based on the guidelines of American College of Medical Genetics and Genomics,it was classified as likely pathogenic(PM1+PM2_Supporting+PM6+PP3),which had been included in the ClinVar database.Proband 2 had a heterozygous mutation of COL4A5 gene c.4913G>A(p.Cys1638Tyr),which was inherited from his mother and had been reported and recorded as a possible cause of disease.The results of prenatal diagnosis in family 1 suggested that the fetus was a female and she had the same heterozygous variant as her mother.After genetic counseling,family 2 chose PGD to give birth to offspring,MARSALA detected and transplanted an embryo without specific genetic abnormalities and chromosomal euploidy,and succeeded in pregnancy.And the prenatal diagnosis results were consistent with PGD results.And the prenatal diagnosis results were consistent with the PGD results.Conclusion In this study,we identify the molecular etiology in two families with Alport syndro

关 键 词：ALPORT综合征 COL4A5基因 胚胎植入前遗传学诊断 

分 类 号：R71[医药卫生—妇产科学]