Non-invasive prenatal testing of pregnancies at risk for phenylketonuria
Non-invasive prenatal testing of pregnancies at risk for phenylketonuria
复制标题
对有苯丙酮尿症风险的妊娠进行无创产前检测
DOI：
10.1136/archdischild-2017-313929
复制
发表时间：
2019-01-01
影响因子：
4.4
通讯作者：
Kong, Xiangdong
中科院分区：
文献类型：
--
作者：
Duan, Huikun;Liu, Ning;Kong, Xiangdong
背景苯丙酮尿症（PKU）是一种常见的代谢性疾病，主要由苯丙氨酸羟化酶（PAH）基因突变引起。该研究的目的是使用循环单分子扩增和重测序技术 (cSMART) 设计并验证 PKU 无创产前检测 (NIPT) 的性能。方法 总共招募了 18 对有生育 PKU 孩子遗传风险的夫妇参加研究。通过桑格测序对羊水细胞或绒毛细胞 DNA 进行金标准侵入性产前诊断 (IPD)，针对已知的亲本 PAH 突变。回顾性地，还通过旨在针对 PAH 基因中所有已知 DNA 变异的多重 cSMART 检测，对来自 18 次妊娠的储存母体血浆样本进行了 NIPT。结果 以 IPD 结果为基准，NIPT 正确对所有胎儿进行了基因分型，包括 6 个 PKU 复合杂合子、4 个 PKU 正常非携带者和 8 个 PKU 杂合子携带者，其中 5 例为母系遗传突变，3 例为父系遗传突变。结论 NIPT cSMART PKU 检测对于突变检测和胎儿基因型的正确分配具有高度敏感性和特异性。基于 PAH 基因的全面突变覆盖，该检测最初可能具有临床实用性，可作为高风险携带者夫妇的妊娠筛查测试。
Background Phenylketonuria (PKU) is a common metabolic disorder caused predominately by mutations in the phenylalanine hydroxylase (PAH) gene. The aim of the study was to design and validate the performance of a non-invasive prenatal test (NIPT) for PKU using circulating single molecule amplification and resequencing technology (cSMART). Methods A total of 18 couples at genetic risk for having a child with PKU were recruited to the study. Gold standard invasive prenatal diagnosis (IPD) was performed on amniocyte or villus cell DNA by Sanger sequencing, targeting the known parental PAH mutations. Retrospectively, NIPT was also performed on stored maternal plasma samples from the 18 pregnancies by a multiplex cSMART assay designed to target all known DNA variants in the PAH gene. Results Benchmarking against IPD results, NIPT correctly genotyped all fetuses, including six compound heterozygotes with PKU, four normal non-carriers of PKU and eight heterozygote carriers of PKU comprising five cases of a maternally inherited mutation and three cases of a paternally inherited mutation. Conclusions The NIPT cSMART PKU assay was highly sensitive and specific for mutation detection and correct assignment of fetal genotypes. Based on comprehensive mutation coverage across the PAH gene, the assay may initially have clinical utility as a pregnancy screening test for high-risk carrier couples.