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A <jats:italic>TTC5<\/jats:italic> role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co\u2010activator complex activity, similarly to what was observed in Menke\u2010Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of <jats:italic>CREBBP<\/jats:italic> and <jats:italic>EP300<\/jats:italic>, which code for the TTC5\u2010binding region. Recently, <jats:italic>TTC5\u2010<\/jats:italic>related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent <jats:italic>TTC5<\/jats:italic> variants. The deep characterization of the molecular and phenotypic spectrum confirmed <jats:italic>TTC5<\/jats:italic>\u2010related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre\u2010 and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published <jats:italic>TTC5<\/jats:italic> cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The <jats:italic>TTC5<\/jats:italic> clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.<\/jats:p>","DOI":"10.1002\/ajmg.a.62852","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T10:52:15Z","timestamp":1654599135000},"page":"2652-2665","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>TTC5<\/i> syndrome: Clinical and molecular spectrum of a severe and recognizable condition"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2742-1484","authenticated-orcid":false,"given":"Luciana","family":"Musante","sequence":"first","affiliation":[{"name":"Institute for Maternal and Child Health \u2010 IRCCS \u201cBurlo Garofolo\u201d  Trieste 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