{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:32:16Z","timestamp":1771068736666,"version":"3.50.1"},"reference-count":46,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T00:00:00Z","timestamp":1723852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100018925","name":"Health Commission of Henan Province","doi-asserted-by":"publisher","award":["SBGJ202102097"],"award-info":[{"award-number":["SBGJ202102097"]}],"id":[{"id":"10.13039\/100018925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Prenatal Diagnosis"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The clinical performance of RHDO\u2010based NIPD for PKU during early gestation remains under\u2010evaluated. Furthermore, studies focused on SNP loci obtained by next\u2010generation sequencing to analyze the genetic evolution of pathogenic variations in PKU is limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Maternal peripheral blood, along with proband and paternal samples, was collected between 7 and 12\u00a0weeks of gestation. The <jats:italic>PAH<\/jats:italic> gene and surrounding high heterozygosity SNPs were targeted for enrichment and sequencing. Fetal genotypes were inferred using RHDO\u2010based NIPD. High\u2010resolution <jats:italic>PAH<\/jats:italic> haplotypes were used for the analysis of two common pathogenic variants in the Chinese population: c.728G&gt;A and c.1238G&gt;C.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixty one PKU families participated with an average fetal fraction of 6.08%. The median gestational age was 8<jats:sup>+6<\/jats:sup>\u00a0weeks. RHDO\u2010based NIPD successfully identified fetal genotypes in 59 cases (96.72%, 59\/62). Two cases failed because of insufficient informative SNPs. In addition, a recombination event was assessed in one fetus of 59 cases. Six, and three haplotypes were identified for c.728G&gt;A(p.Arg243Gln) and c.1238G&gt;C(p.Arg413Pro), respectively. Hap_3 and hap_8 were identified as the ancestral haplotypes for these pathogenic variants, with other haplotypes arising from mutations or recombination based on these ancestral haplotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study validates the feasibility of an RHDO\u2010based assay for NIPD of PKU in early pregnancy and introduces its application in the demonstration of founder effects in recurrent pathogenic variations, offering new insights into the evolutionary analysis of <jats:italic>PAH<\/jats:italic> variations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pd.6645","type":"journal-article","created":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T16:05:08Z","timestamp":1723910708000},"page":"1198-1209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High\u2010Resolution Haplotyping of the <i>PAH<\/i> Gene Enables Early Gestation Noninvasive Prenatal Diagnosis of Phenylketonuria and Evolution Analysis of Recurrent Pathogenic Variations"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8268-3365","authenticated-orcid":false,"given":"Jingqi","family":"Zhu","sequence":"first","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenhua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaojun","family":"Li","sequence":"additional","affiliation":[{"name":"Celula (China) Medical Technology Co., Ltd  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Celula (China) Medical Technology Co., Ltd  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-1100","authenticated-orcid":false,"given":"Lingrong","family":"Kong","sequence":"additional","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"},{"name":"Department of Fetal Medicine &amp; Prenatal Diagnosis Center Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecologic Oncology Shanghai First Maternity and Infant Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4322-914X","authenticated-orcid":false,"given":"Xinyu","family":"Fu","sequence":"additional","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanyun","family":"Li","sequence":"additional","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Feng","sequence":"additional","affiliation":[{"name":"Celula (China) Medical Technology Co., Ltd  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiqin","family":"Tang","sequence":"additional","affiliation":[{"name":"Celula (China) Medical Technology Co., Ltd  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Celula (China) Medical Technology Co., Ltd  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0030-7638","authenticated-orcid":false,"given":"Xiangdong","family":"Kong","sequence":"additional","affiliation":[{"name":"Genetic and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/137.6.1561s"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010021\u201000267\u20100"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcl.2018.12.016"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2005.06.004"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(97)02174\u20100"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2012.189589"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.791856"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6124"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2016.195"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild\u20102017\u2010313929"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471\u20100528.15869"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216\u2010019\u201002087\u20104"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920\u2010021\u201001091\u2010x"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201018358\u2010y"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920\u2010021\u201001141\u20104"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep15769"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038\u2010004\u20100197\u20105"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2008.40.5.533"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2011.10"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.09.001"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.11.158"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9113"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.102623"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/edm2.396"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2012_178"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2013.01.006"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9116"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2013_284"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1993.1295"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.408"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.03.015"},{"issue":"4","key":"e_1_2_10_33_1","first-page":"619","article-title":"Extensive Restriction Site Polymorphism at the Human Phenylalanine Hydroxylase Locus and Application in Prenatal Diagnosis of Phenylketonuria","volume":"37","author":"Lidsky A. 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