全基因组测序用于肾脏异常胎儿的产前诊断

Prenatal diagnosis of fetuses with renal anomalies by whole genome sequencing

目的应用全基因组测序技术对4例肾脏异常胎儿进行遗传学检测,以寻找其可能的遗传学病因。方法对4例肾脏异常胎儿的孕妇抽取羊水及胎儿父母外周血进行DNA提取,行全基因组测序检测,根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)原则对数据进行判定,拷贝数变异结果与SNP-array结果进行比对,致病性点变异行Sanger测序验证。结果全基因组测序技术检测2例胎儿为拷贝数变异致病,分别为染色体17q12缺失1.45 Mb和1q21.1-21.2重复1.85 Mb;2例胎儿为基因变异致病,分别为PKHD1 c.8301del(p.Asn2768Thr fs*18)和c.4481del(p.Asn1494Thrfs*6)复合杂合变异和BBS12:c.1372dup(p.Thr458Asnfs*5)纯合变异。SNP-array和Sanger测序结果与全基因组测序数据一致。根据ACMG遗传变异分类标准与指南,PKHD1 c.8301del(p.Asn2768Thr fs*18)和c.4481del(p.Asn1494Thrfs*6)变异均为致病性变异(PVS1+PM2+PM3+PP4),BBS12:c.1372dup(p.Thr458Asnfs*5)变异判定为可能致病性变异(PVS1+PM2)。结论全基因组测序技术可以高效快速的为产前肾脏异常胎儿提供遗传学诊断,并为遗传咨询提供依据。

Objective To explore the genetic basis for fetuses with renal anomalies.Methods Genomic DNA of four fetuses and their parents was extracted from amniotic fluid and peripheral blood samples and subjected to whole genome sequencing.Candidate variants were predicted according to the American College of Medical Genetics and Genomics(ACMG)guidelines and validated by SNP-array and Sanger sequencing.Results Two fetuses were found to carry a 1.45 Mb pathogenic microdeletion in 17q12 and a pathogenic 1.85 Mb microduplication at 1q21.1-21.2,respectively.One fetus was found to harbor compound heterozygous variants c.8301del(p.Asn2768Thrfs*18)and c.4481del(p.Asn1494Thrfs*6)of the PKHD1 gene,which were predicted to be pathogenic.And one fetus has harbored homozygous c.1372dup(p.Thr458Asnfs*5)variants of the BBS12 gene,which was predicted to be likely pathogenic.All variants were validated by Sanger sequencing.Conclusion Whole genome sequencing can enable efficient prenatal diagnosis for fetuses with renal anomalies with high accuracy.