{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T12:46:09Z","timestamp":1782305169219,"version":"3.54.5"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2026,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n \n Pitt\u2013Hopkins Syndrome (PTHS) is a rare genetic disorder primarily caused by\n TCF4<\/jats:italic>\n mutations and involves developmental, intellectual, and physical changes in children. Increased nuchal translucency (NT) has not been associated with\n TCF4<\/jats:italic>\n mutations or PTHS. Here we study the connection between increased NT and a c.1146+3A>T mutation in the\n TCF4<\/jats:italic>\n gene.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The genetic basis of increased NT in an early pregnancy fetus was investigated by family trio clinical exome sequencing (CES) using fetal amniotic fluid and parental peripheral blood samples. The candidate variant was validated by Sanger sequencing. The impact of the variant on transcription was assessed using a minigene assay.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Early ultrasound revealed an NT measurement of 3.5\u2009mm in fetus B of a twin pregnancy. CES identified a de novo heterozygous c.1146+3A>T variant in intron 14 of\n TCF4<\/jats:italic>\n , confirmed by Sanger sequencing. In\u00a0vitro minigene experiments showed that the mutation disrupted\n TCF4<\/jats:italic>\n mRNA splicing, resulting in exon 14 skipping and a truncated transcript.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our results identified c.1146+3A>T as a novel splicing variant of the\n TCF4<\/jats:italic>\n . The\n TCF4<\/jats:italic>\n c.1146+3A>T mutation may underlie increased NT in early pregnancy, suggesting that increased NT could be an early intrauterine sign of PTHS.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mgg3.70239","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:22:03Z","timestamp":1780035723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Analysis of\n P<\/scp>\n itt\u2013\n H<\/scp>\n opkins Syndrome Caused by a Novel Splicing Variant (\n c.<\/scp>\n 1146+\n 3A<\/scp>\n >\n T<\/scp>\n ) in the\n TCF4<\/i>\n Gene"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7258-1701","authenticated-orcid":false,"given":"Wenlong","family":"Shen","sequence":"first","affiliation":[{"name":"Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Center, Department of Genetic and Genomic Medicine Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Center, Department of Genetic and Genomic Medicine Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaer","family":"Lv","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Center, Department of Genetic and Genomic Medicine Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Tang","sequence":"additional","affiliation":[{"name":"Hangzhou Medical College Hangzhou Zhejiang China"},{"name":"Laboratory Medicine Center, Department of Genetic and Genomic Medicine Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63098"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63920"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jdn.70044"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2017.08.004"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20935"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100883"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn113903\u201020220321\u201000273"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6414"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43042-024-00586-3"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.27715"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3877\/cma.j.issn.1672\u20106448.2022.11.008"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34070"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds112"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2020.104088"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2024.104313"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00438\u2010022\u201001948\u20105"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010024\u201003055\u20107"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010024\u201003383\u20108"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13506"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1086\/515583"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.060129"}],"container-title":["Molecular 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