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Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274\u2009A\u2009&gt;\u2009G p.(K91E) variant in <jats:italic>HIST1H4J<\/jats:italic>, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on <jats:italic>HIST1H4J<\/jats:italic> underlies a human syndrome that is genetically and phenotypically akin to the <jats:italic>HIST1H4C<\/jats:italic>-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in <jats:italic>HIST1H4C<\/jats:italic>. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone <jats:italic>H4<\/jats:italic> genes for vertebrate development.<\/jats:p>","DOI":"10.1038\/s41431-019-0552-9","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T14:02:48Z","timestamp":1575554568000},"page":"674-678","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9975-0546","authenticated-orcid":false,"given":"Federico","family":"Tessadori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atteeq U.","family":"Rehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques C.","family":"Giltay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-9851","authenticated-orcid":false,"given":"Fan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Streff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Duran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9418-0422","authenticated-orcid":false,"given":"Jeroen","family":"Bakkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-0329","authenticated-orcid":false,"given":"Gijs","family":"van Haaften","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"key":"552_CR1","doi-asserted-by":"publisher","first-page":":1442","DOI":"10.1038\/s41588-018-0220-y","volume":"50","author":"MF Basilicata","year":"2018","unstructured":"Basilicata MF, Bruel AL, Semplicio G, Valsecchi CIK, Aktas T, Duffourd Y, et al. 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The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}