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Common polymorphisms in <jats:italic>TCF4<\/jats:italic> and disruptive variants in the proximal region of the gene have been linked to relatively mild neuropsychiatric or neurodevelopmental disorders. In contrast, variants impacting distal exons are associated with Pitt\u2013Hopkins syndrome (PTHS), a severe autosomal dominant condition characterized by profound intellectual disability, developmental delay, limited or absent speech, distinctive facies, and disordered breathing. Although phenotypic variability has been observed in PTHS, intellectual impairment and significant speech and motor delays are invariably present. In contrast to the typical de novo variants causing <jats:italic>TCF4<\/jats:italic>\u2010related disorder and PTHS, we report a familial form of <jats:italic>TCF4<\/jats:italic>\u2010related disorder where the missense variant arose de novo in the father and was inherited by two of his children. Although this family's variant's position in exon 18 predicted a typical PTHS phenotype, none of the affected individuals met the clinical diagnostic criteria for PTHS suggested by Zollino et al. in the first international consensus statement (as in the study by Zollino et al. in 2019). Rather, the three affected family members exhibited remarkably variable and milder phenotypes than would have been predicted from the position of their <jats:italic>TCF4<\/jats:italic> variant. Thus, the clinical spectrum of PTHS\u2010associated <jats:italic>TCF4<\/jats:italic> variants may be broader than previously reported.<\/jats:p>","DOI":"10.1002\/ajmg.a.63098","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T23:00:35Z","timestamp":1672182035000},"page":"1070-1076","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A typical variant in <i>TCF4<\/i> exon 18 is not associated with <scp>P<\/scp>itt\u2013<scp>H<\/scp>opkins syndrome but with a familial case of mild and nonspecific neurodevelopmental disorder"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8131-1083","authenticated-orcid":false,"given":"Abdulrahman A.","family":"Aldeeri","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Internal Medicine King Saud University Medical City  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Abu\u2010El\u2010Haija","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/515582"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32318"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2018.08.026"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20935"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0422-2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073817750490"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32212"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2020.00042"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0096-4"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2022.104458"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21103694"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29942-w"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpc.1978.14.3.182"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14206"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0526-11.2011"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1358-4"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21639"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2012.39"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-021-00651-8"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13506"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63098","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.63098","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63098","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T23:04:33Z","timestamp":1692399873000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/ajmg.a.63098"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63098","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]},"assertion":[{"value":"2022-08-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}