{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:50:49Z","timestamp":1788306649501,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Xia\u2010Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT\u2010hook DNA\u2010binding motif\u2010containing 1 gene (<jats:italic>AHDC1<\/jats:italic>), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. <jats:italic>AHDC1<\/jats:italic> variants possibly act through a dominant\u2010negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N\u2010terminal are thought to determine a milder phenotype with better cognitive performances. However, clean\u2010cut genotype\u2013phenotype correlations are still lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Cases<\/jats:title><jats:p>In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in <jats:italic>AHDC1<\/jats:italic>. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In this study, we report uncommon XGS features associated with five novel truncating variants in <jats:italic>AHDC<\/jats:italic>, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype\u2013phenotype correlations in XGS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2058","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T10:54:10Z","timestamp":1655549650000},"page":"759-767","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Genotype\u2013phenotype spectrum and correlations in <scp>Xia\u2010Gibbs<\/scp> syndrome: Report of five novel cases and literature review"],"prefix":"10.1002","volume":"114","author":[{"given":"Ferruccio","family":"Romano","sequence":"first","affiliation":[{"name":"Medical Genetics Unit IRCCS Istituto Giannina Gaslini  Genoa Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariateresa","family":"Falco","sequence":"additional","affiliation":[{"name":"U.O.S.D. 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San Pio  Benevento 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":"Maria Cristina","family":"Digilio","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Medical Genetics and Rare Disease Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Lisa","family":"Dentici","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Medical Genetics and Rare Disease Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Alfieri","sequence":"additional","affiliation":[{"name":"Neuropsichiatric Unit,\u00a0Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Agolini","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Garavelli","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit Azienda USL\u2010IRCCS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Accogli","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Specialized Medicine McGill University  Quebec Canada"},{"name":"Department of Human Genetics McGill University  Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"TUDP","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa  Genoa Italy"},{"name":"Pediatric Neurology and Muscular Diseases Unit IRCCS Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Scarano","sequence":"additional","affiliation":[{"name":"U.O.S.D. 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