Genetics and Prenatal Diagnosis Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Research and Development Department, Berry Genomics Corporation, Beijing, China.
Arch Dis Child Fetal Neonatal Ed. 2019 Jan;104(1):F24-F29. doi: 10.1136/archdischild-2017-313929. Epub 2018 Jan 20.
Phenylketonuria (PKU) is a common metabolic disorder caused predominately by mutations in the phenylalanine hydroxylase () 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).
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 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 gene.
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.
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 gene, the assay may initially have clinical utility as a pregnancy screening test for high-risk carrier couples.
苯丙酮尿症（PKU）是一种常见的代谢疾病，主要由苯丙氨酸羟化酶（）基因突变引起。本研究旨在设计并验证使用循环单分子扩增和重测序技术（cSMART）进行非侵入性产前检测（NIPT）用于 PKU 的性能。
共招募 18 对具有 PKU 患儿遗传风险的夫妇参加研究。通过 Sanger 测序对羊水细胞或绒毛细胞 DNA 进行金标准的侵袭性产前诊断（IPD），针对已知的父母突变进行检测。回顾性地，通过设计靶向所有已知基因变异的多重 cSMART 检测，对 18 例妊娠的储存母血浆样本进行 NIPT。
与 IPD 结果进行基准测试，NIPT 正确地对所有胎儿进行了基因分型，包括 6 例 PKU 复合杂合子、4 例 PKU 正常非携带者和 8 例 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。
NIPT cSMART PKU 检测在突变检测和胎儿基因型的正确分配方面具有高度的敏感性和特异性。基于整个基因的全面突变覆盖，该检测最初可能具有临床效用，作为高危携带者夫妇的妊娠筛查检测。
