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EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by <jats:italic>TP63<\/jats:italic>. Here, we report a patient with an EEC\/AEC syndrome\u2010like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in <jats:italic>TP63<\/jats:italic> nor CNVs at the <jats:italic>TP63<\/jats:italic> locus were identified. Exome sequencing revealed de novo heterozygous variants in <jats:italic>CHUK<\/jats:italic> (conserved helix\u2010loop\u2010helix ubiquitous kinase), <jats:italic>PTGER4<\/jats:italic>, and <jats:italic>IFIT2<\/jats:italic>. While the variant in <jats:italic>PTGER4<\/jats:italic> might contribute to the immunodeficiency and growth delay, the variant in <jats:italic>CHUK<\/jats:italic> appeared to be most relevant for the EEC\/AEC\u2010like phenotype. <jats:italic>CHUK<\/jats:italic> is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF\u2010\u03baB pathway activation. The identified <jats:italic>CHUK<\/jats:italic> variant (g.101980394T&gt;C; c.425A&gt;G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF\u2010\u03baB pathway; (2) it affects the feedback loop of the canonical and non\u2010canonical NF\u2010\u03baB pathways that are CHUK kinase activity\u2010dependent; and (3) it disrupts NF\u2010\u03baB independent epidermal development that is often p63\u2010dependent. Therefore, we propose that the heterozygous <jats:italic>CHUK<\/jats:italic> variant is highly likely to be causative to the EEC\/AEC\u2010like and additional hypogammaglobulinemia phenotypes in the patient presented here.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.38274","type":"journal-article","created":{"date-parts":[[2017,5,17]],"date-time":"2017-05-17T15:57:04Z","timestamp":1495036624000},"page":"1813-1820","source":"Crossref","is-referenced-by-count":14,"title":["Identification of a de novo variant in <i>CHUK<\/i> in a patient with an EEC\/AEC syndrome\u2010like phenotype and hypogammaglobulinemia"],"prefix":"10.1002","volume":"173","author":[{"given":"Kriti D.","family":"Khandelwal","sequence":"first","affiliation":[{"name":"Department of Orthodontics and Craniofacial Biology Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte W.","family":"Ockeloen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanka","family":"Venselaar","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Biomolecular Informatics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Boulanger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Haematology and Oncology, Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Brichard","sequence":"additional","affiliation":[{"name":"Department of Pediatric Haematology and Oncology, Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Sokal","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Catholique de Louvain, Cliniques Universitaires St Luc Service de Gastroent\u00e9rologie et H\u00e9patologie P\u00e9diatrique Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolph","family":"Pfundt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Rinne","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"van Beusekom","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon","family":"Bloemen","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Craniofacial Biology Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"Vriend","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Biomolecular Informatics Radboud university medical center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Revencu","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics Cliniques universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine E. 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