{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:08:27Z","timestamp":1747188507632,"version":"3.40.5"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>TCF4<\/jats:italic> haploinsufficiency by deletions, truncating variants or loss\u2010of\u2010function missense variants within the DNA\u2010binding and protein interacting bHLH domain causes Pitt\u2010Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N\u2010terminus of <jats:italic>TCF4<\/jats:italic> were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, <jats:italic>de novo<\/jats:italic> missense variant c.1165C\u2009&gt;\u2009T, p.(Arg389Cys) in <jats:italic>TCF4<\/jats:italic>. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non\u2010specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator\u2010recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype\u2013phenotype correlation for <jats:italic>TCF4<\/jats:italic>\u2010related NDDs.<\/jats:p>","DOI":"10.1111\/cge.14206","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T03:48:15Z","timestamp":1659239295000},"page":"517-523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The recurrent <scp><i>TCF4<\/i><\/scp> missense variant p.(<scp>Arg389Cys<\/scp>) causes a neurodevelopmental disorder overlapping with but not typical for <scp>Pitt\u2010Hopkins<\/scp> syndrome"],"prefix":"10.1111","volume":"102","author":[{"given":"Bernt","family":"Popp","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University of Leipzig Medical Center  Leipzig Germany"},{"name":"Center of Functional Genomics Berlin Institute of Health at Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5953-2728","authenticated-orcid":false,"given":"Thierry","family":"Bienvenu","sequence":"additional","affiliation":[{"name":"INSERM U1266, Institut de Psychiatrie et de Neurosciences de Paris Universit\u00e9 de Paris  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Giurgea","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique M\u00e9dicale INSERM Childhood Genetic Diseases, AP\u2010HP. Sorbonne Universit\u00e9, H\u00f4pital Trousseau  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Metreau","sequence":"additional","affiliation":[{"name":"APHP, Service de Neurologie P\u00e9diatrique H\u00f4pital Universitaire Bicetre  Le Kremlin\u2010Bicetre France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia","family":"Kraus","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Reis","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics University Hospital Carl Gustav Carus at the Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Palomares","family":"Bralo","sequence":"additional","affiliation":[{"name":"INGEMM, Institute of Medical and Molecular Genetics Hospital Universitario La Paz, IDIPAZ  Madrid Spain"},{"name":"ITHACA European Reference Network  Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-2316","authenticated-orcid":false,"given":"Jair","family":"Tenorio\u2010Casta\u00f1o","sequence":"additional","affiliation":[{"name":"INGEMM, Institute of Medical and Molecular Genetics Hospital Universitario La Paz, IDIPAZ  Madrid Spain"},{"name":"ITHACA European Reference Network  Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-4825","authenticated-orcid":false,"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"INGEMM, Institute of Medical and Molecular Genetics Hospital Universitario La Paz, IDIPAZ  Madrid Spain"},{"name":"ITHACA European Reference Network  Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berta","family":"Almoguera","sequence":"additional","affiliation":[{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"},{"name":"Department of Genetics and Genomics Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fermina","family":"Lopez\u2010Grondona","sequence":"additional","affiliation":[{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras ISCIII  Madrid Spain"},{"name":"Department of Genetics and Genomics Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8002-2020","authenticated-orcid":false,"given":"Christiane","family":"Zweier","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"Department of Human Genetics Inselspital, Bern University Hospital, University of Bern  Bern Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"issue":"3","key":"e_1_2_7_2_1","first-page":"182","article-title":"A syndrome of mental retardation, wide mouth and intermittent overbreathing","volume":"14","author":"Pitt D","year":"1978","journal-title":"Aust Paediatr J"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/515582"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1086\/515583"},{"key":"e_1_2_7_5_1","unstructured":"SweetserDA ElsharkawiI YonkerL SteevesM ParkinK ThibertR.Pitt\u2010Hopkins Syndrome. 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