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To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of <jats:italic>PHF6<\/jats:italic>, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR\/Cas9 to induce knockout of <jats:italic>PHF6<\/jats:italic> in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of <jats:italic>PHF6<\/jats:italic> loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.<\/jats:p>","DOI":"10.1038\/s41598-020-75999-2","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T11:03:36Z","timestamp":1604487816000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Loss of PHF6 leads to aberrant development of human neuron-like cells"],"prefix":"10.1038","volume":"10","author":[{"given":"Anna","family":"Fliedner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Gregor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulvia","family":"Ferrazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arif B.","family":"Ekici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Zweier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"75999_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.0954-6820.1962.tb04162.x","volume":"171","author":"M B\u00f6rjeson","year":"1962","unstructured":"B\u00f6rjeson, M., Forssman, H. & Lehmann, O. 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