{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:19:05Z","timestamp":1789165145240,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2025,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n RALA is a small GTPase from the RAS superfamily implicated in signal transduction and cytoskeletal dynamics. Recently, de novo variants in\n RALA<\/jats:italic>\n have been associated with a neurodevelopmental syndrome characterized by intellectual disability (ID), developmental delay (DD), and seizures. So far, only <\u200912 patients have been reported.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study, we report two novel patients with neurodevelopmental impairment and epilepsy carrying previously unreported\n RALA<\/jats:italic>\n variants. We performed a thorough clinical investigation of these patients and performed brain MRI to detect potential abnormalities. Trio\u2010exome sequencing and\/or NGS panel testing were conducted to identify the genetic variants. Then, we reviewed previous cases reported in the literature.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Affected individuals showed a complex neurodevelopmental phenotype consistent with Hiatt\u2010Neu\u2010Cooper neurodevelopmental syndrome. Brain MRI in both subjects showed abnormalities including megalencephaly and ventricular enlargement, previously unreported in\n RALA<\/jats:italic>\n patients. Genetic testing revealed two novel de novo missense variants in\n RALA<\/jats:italic>\n : c.217G>A, p.(Glu73Lys) in case #1 and c.73G>C, p.(Val25Leu) in case #2. Both variants affect highly conserved residues within the GTP\/GDP\u2010binding site of the protein. These changes are predicted to be deleterious by in silico tools, interfering with the GTPase activity of RALA.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our findings expand the genotype and phenotype spectrum of Hiatt\u2010Neu\u2010Cooper neurodevelopmental syndrome. Our observations also support the important role of variants affecting the GTP\/GDP\u2010binding site of the RALA protein in the pathogenesis of Hiatt\u2010Neu\u2010Cooper neurodevelopmental syndrome.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mgg3.70072","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T16:33:27Z","timestamp":1738946007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel De Novo\n \n RALA<\/i>\n <\/scp>\n Missense Variants Expand the Genotype Spectrum of Hiatt\u2010Neu\u2010Cooper Neurodevelopmental Syndrome"],"prefix":"10.1002","volume":"13","author":[{"given":"Alice","family":"Dainelli","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-0601","authenticated-orcid":false,"given":"Mohammad Sadegh Shams","family":"Nosrati","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferruccio","family":"Romano","sequence":"additional","affiliation":[{"name":"Genomics and Clinical Genetics IRCCS Istituto Giannina Gaslini Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6980-3248","authenticated-orcid":false,"given":"Fabiana","family":"Vercellino","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit SS Antonio e Biagio e Cesare Arrigo Hospital Alessandria 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[{"name":"Genomics and Clinical Genetics IRCCS Istituto Giannina Gaslini Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa 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":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa 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