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We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole\u2010exome sequencing analysis identified a novel heterozygous frameshift insertion in <jats:italic>ALX4<\/jats:italic> (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2\u2010causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt\/\u03b2\u2010catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT\/\u03b2\u2010catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants\u00a0in <jats:italic>ALX4<\/jats:italic> exerting a gain\u2010of\u2010function effect.<\/jats:p>","DOI":"10.1002\/ajmg.a.63408","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T11:48:02Z","timestamp":1695124082000},"page":"2806-2812","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dominant frontonasal dysplasia with ectodermal defects results from increased activity of <i>ALX4<\/i>"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6158-1089","authenticated-orcid":false,"given":"Alon","family":"Peled","sequence":"first","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-2091","authenticated-orcid":false,"given":"Ofer","family":"Sarig","sequence":"additional","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9849-7566","authenticated-orcid":false,"given":"Janan","family":"Mohamad","sequence":"additional","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"},{"name":"Department of Human Molecular Genetics and Biochemistry Tel\u2010Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0507-1505","authenticated-orcid":false,"given":"Marina","family":"Eskin\u2010Schwartz","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben Gurion University of the Negev  Be'er Sheva Israel"},{"name":"Soroka University Medical Center Genetic Institute  Be'er Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2568-1098","authenticated-orcid":false,"given":"Dan","family":"Vodo","sequence":"additional","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1753-0182","authenticated-orcid":false,"given":"Ron","family":"Bochner","sequence":"additional","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1103-476X","authenticated-orcid":false,"given":"Natalya","family":"Malchin","sequence":"additional","affiliation":[{"name":"Division of Dermatology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofer","family":"Isakov","sequence":"additional","affiliation":[{"name":"Rabin Medical Center Raphael Recanati Genetic Institute  Petach Tikva Israel"},{"name":"Clalit Research Institute, Clalit Health Services  Ramat Gan Israel"},{"name":"The Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9913-6124","authenticated-orcid":false,"given":"Noam","family":"Shomron","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel\u2010Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-6483","authenticated-orcid":false,"given":"Gilad","family":"Fainberg","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5927-6998","authenticated-orcid":false,"given":"Marta","family":"Bertolini","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of M\u00fcnster  M\u00fcnster Germany"},{"name":"Monasterium Laboratory, Nano\u2010Bioanalytik Zentrum  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-9358","authenticated-orcid":false,"given":"Ralf","family":"Paus","sequence":"additional","affiliation":[{"name":"Monasterium Laboratory, Nano\u2010Bioanalytik Zentrum  M\u00fcnster Germany"},{"name":"Dr Phillip Frost Department of Dermatology &amp; 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