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In mammals, TREX is essential during embryogenesis, determining stem cell fate specification by regulating posttranscriptional self\u2010renewal and differentiation in several tissues. It is composed of a core called THO, consisting of THOC1, 2, 5, 6, 7, and additional proteins. Bi\u2010allelic mutations in <jats:italic>THOC6<\/jats:italic> have been associated to Beaulieu\u2013Boycott\u2013Innes syndrome (BBIS), a syndromic form of intellectual disability (ID). To date, nine patients harbouring homozygous or compound heterozygous mutations in <jats:italic>THOC6<\/jats:italic> have been reported. Despite the clinical heterogenity and subtle dysmorphic features in some individuals, distinctive facial features are tall forehead, short and upslanting palpebral fissures, deep set eyes, flat philtrum, and malocclusion. Nonlife threatening congenital anomalies are common, including cardiac and renal malformations, anteriorly displaced anus, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Affected patients usually have short stature, mild microcephaly, and mild to moderate ID. Here, we describe an Italian patient with BBIS, carrying two compound heterozygous loss\u2010of\u2010function (LoF) variants in <jats:italic>THOC6<\/jats:italic> (c.577C\u2009&gt;\u2009T, p.R193* and c.792_793delCA, p.V264Vfs*48). In addition to the common phenotype, she displays cerebellar hypoplasia with severe vermian dysgenesis and hydrocephalus due to aqueductal stenosis, multiple skeletal anomalies and hypergonadotropic hypogonadism. Thus, we review the previous cases and discuss the phenotypic spectrum of BBIS, providing further evidence regarding the pivotal role of TREX complex in human development.<\/jats:p>","DOI":"10.1002\/ajmg.a.40534","type":"journal-article","created":{"date-parts":[[2018,9,21]],"date-time":"2018-09-21T21:34:07Z","timestamp":1537565647000},"page":"2835-2840","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel CNS malformations and skeletal anomalies in a patient with Beaulieu\u2010boycott\u2010Innes syndrome"],"prefix":"10.1002","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-6721","authenticated-orcid":false,"given":"Andrea","family":"Accogli","sequence":"first","affiliation":[{"name":"UOC Neurochirurgia Istituto Giannina Gaslini  Genoa Italy"},{"name":"Universit\u00e0 degli studi di Genova  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2194-7239","authenticated-orcid":false,"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[{"name":"UOC Neurochirurgia Istituto Giannina Gaslini  Genoa Italy"},{"name":"Universit\u00e0 degli studi di Genova  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Calcagno","sequence":"additional","affiliation":[{"name":"UOC Clinica Pediatrica Istituto Giannina Gaslini, Universit\u00e0 di Genova  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Castello","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalaura","family":"Torella","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"},{"name":"Department of Precision Medicine University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Musacchia","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M. E.","family":"Allegri","sequence":"additional","affiliation":[{"name":"UOC Clinica Pediatrica Istituto Giannina Gaslini, Universit\u00e0 di Genova  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria M.","family":"Mancardi","sequence":"additional","affiliation":[{"name":"UOC Neuropsichiatria Infantile\u2014Centro Epilessia Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"UOC Clinica Pediatrica Istituto Giannina Gaslini, Universit\u00e0 di Genova  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariasavina","family":"Severino","sequence":"additional","affiliation":[{"name":"UOC Neuroradiologia Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Telethon Undiagnosed Diseases Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"},{"name":"Department of Precision Medicine University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[{"name":"UOC Neurochirurgia Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12793"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2016.113"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37549"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12987"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-8-62"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33379"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0000000000000134"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052447"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-101542"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14974"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.10.004"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160010"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.276030.115"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws065"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.05.021"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104974"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-8-1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1302205"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516767"},{"key":"e_1_2_8_21_1","first-page":"11.10.1","article-title":"From FastQ data to high confidencevariantcalls: The genome analysis toolkit best practicespipeline","volume":"43","author":"Van derAuwera G. 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