{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:08:56Z","timestamp":1787162936293,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T00:00:00Z","timestamp":1563926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["08C208"],"award-info":[{"award-number":["08C208"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["08C305"],"award-info":[{"award-number":["08C305"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010787","name":"Associazione Italiana Rett","doi-asserted-by":"publisher","award":["National Grant 2012"],"award-info":[{"award-number":["National Grant 2012"]}],"id":[{"id":"10.13039\/100010787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40\u201373% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels\/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants\u2014one in GABRB2 and, for first time, one in GABRG2\u2014were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT\/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical\/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.<\/jats:p>","DOI":"10.3390\/ijms20153621","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T10:48:19Z","timestamp":1563965299000},"page":"3621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett\/Rett-like Phenotypes"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-5445","authenticated-orcid":false,"given":"Francesca","family":"Cogliati","sequence":"first","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Giorgini","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Masciadri","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Bonati","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Service of Medical Genetics, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-8534","authenticated-orcid":false,"given":"Margherita","family":"Marchi","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"},{"name":"Neuroalgology Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Cracco","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Gentilini","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Molecular Biology Laboratory, Unit of Bioinformatic and Statistical Genomic, 20095 Cusano Milanino, Italy"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1769-6548","authenticated-orcid":false,"given":"Angela","family":"Peron","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"},{"name":"Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, UT 84101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam Nella","family":"Savini","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigina","family":"Spaccini","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Obstetrics and Gynecology, V. Buzzi Children\u2019s Hospital, University of Milan, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-0077","authenticated-orcid":false,"given":"Barbara","family":"Scelsa","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Maitz","sequence":"additional","affiliation":[{"name":"Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edvige","family":"Veneselli","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children\u2019s Sciences, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Prato","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children\u2019s Sciences, Istituto Giannina Gaslini, University of Genoa, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pintaudi","sequence":"additional","affiliation":[{"name":"DINOGMI, University of Genova, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Moroni","sequence":"additional","affiliation":[{"name":"Child Neurology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aglaia","family":"Vignoli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-7227","authenticated-orcid":false,"given":"Lidia","family":"Larizza","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-0193","authenticated-orcid":false,"given":"Silvia","family":"Russo","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jpeds.2005.10.037","article-title":"Rett syndrome in Australia: A review of the epidemiology","volume":"148","author":"Laurvick","year":"2006","journal-title":"J. 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