{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:45:04Z","timestamp":1790858704171,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:00:00Z","timestamp":1692835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause intellectual disability with Rett syndrome (RTT)-like features. The aim of this study was to obtain systematic information on the natural history and extra-central nervous system (CNS) manifestations for the Italian IQSEC2 population (&gt;90%) by using structured family interviews and semi-quantitative questionnaires. IQSEC2 encephalopathy prevalence estimate was 7.0 to 7.9 \u00d7 10\u22127. Criteria for typical RTT were met in 42.1% of the cases, although psychomotor regression was occasionally evidenced. Genetic diagnosis was occasionally achieved in infancy despite a clinical onset before the first 24 months of life. High severity in both the CNS and extra-CNS manifestations for the IQSEC2 patients was documented and related to a consistently adverse quality of life. Neurodevelopmental delay was diagnosed before the onset of epilepsy by 1.8 to 2.4 years. An earlier age at menarche in IQSEC2 female patients was reported. Sleep disturbance was highly prevalent (60 to 77.8%), with mandatory co-sleeping behavior (50% of the female patients) being related to de novo variant origin, younger age, taller height with underweight, better social interaction, and lower life quality impact for the family and friends area. In conclusion, the IQSEC2 encephalopathy is a rare and likely underdiagnosed developmental encephalopathy leading to an adverse life quality impact.<\/jats:p>","DOI":"10.3390\/children10091442","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T10:06:48Z","timestamp":1692871608000},"page":"1442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Natural Course of IQSEC2-Related Encephalopathy: An Italian National Structured Survey"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7027-1207","authenticated-orcid":false,"given":"Silvia","family":"Leoncini","sequence":"first","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"},{"name":"Rett Syndrome Trial Center, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9704-7030","authenticated-orcid":false,"given":"Lidia","family":"Boasiako","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"},{"name":"Rett Syndrome Trial Center, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-0482","authenticated-orcid":false,"given":"Diego","family":"Lopergolo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy"},{"name":"UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero Universitaria Senese, Policlinico Le Scotte, 53100 Siena, Italy"},{"name":"IRCCS Stella Maris Foundation, Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, 56018 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3256-6723","authenticated-orcid":false,"given":"Maria","family":"Altamura","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"},{"name":"Rett Syndrome Trial Center, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3145-6414","authenticated-orcid":false,"given":"Caterina","family":"Fazzi","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"},{"name":"Rett Syndrome Trial Center, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-658X","authenticated-orcid":false,"given":"Roberto","family":"Canitano","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Department of Mental Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0974-0596","authenticated-orcid":false,"given":"Salvatore","family":"Grosso","sequence":"additional","affiliation":[{"name":"Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy"},{"name":"Pediatric Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6255-9761","authenticated-orcid":false,"given":"Ilaria","family":"Meloni","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0391-1980","authenticated-orcid":false,"given":"Margherita","family":"Baldassarri","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2963-7809","authenticated-orcid":false,"given":"Susanna","family":"Croci","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-9220","authenticated-orcid":false,"given":"Alessandra","family":"Renieri","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7664-5807","authenticated-orcid":false,"given":"Mario","family":"Mastrangelo","sequence":"additional","affiliation":[{"name":"Maternal Infantile and Urological Sciences Department, Sapienza University of Rome, 00185 Rome, Italy"},{"name":"Child Neurology and Psychiatry Unit, Department of Neurosciences and Mental Health, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9881-3119","authenticated-orcid":false,"given":"Claudio","family":"De Felice","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Women\u2019s and Children\u2019s Health, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"},{"name":"Rett Syndrome Trial Center, University Hospital Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1097\/YPG.0000000000000128","article-title":"IQSEC2 and X-linked syndromal intellectual disability","volume":"26","author":"McDougle","year":"2016","journal-title":"Psychiatr. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1651-2227.2002.tb03120.x","article-title":"X-chromosome inactivation and human genetic disease","volume":"91","author":"Lyon","year":"2002","journal-title":"Acta Paediatr. Suppl."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.gde.2015.04.002","article-title":"X-chromosome inactivation: New insights into cis and trans regulation","volume":"31","author":"Galupa","year":"2015","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature03479","article-title":"X-inactivation profile reveals extensive variability in X-linked gene expression in females","volume":"434","author":"Carrel","year":"2005","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/ng.588","article-title":"Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability","volume":"42","author":"Shoubridge","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1110","DOI":"10.1038\/tp.2017.81","article-title":"Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis","volume":"7","author":"Hinze","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9105","DOI":"10.1074\/jbc.M115.691717","article-title":"Subunit-selective N-Methyl-d-aspartate (NMDA) receptor signaling through brefeldin A-resistant Arf guanine nucleotide exchange factors BRAG1 and BRAG2 during synapse maturation","volume":"291","author":"Elagabani","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11080","DOI":"10.1038\/ncomms11080","article-title":"Bidirectional regulation of synaptic transmission by BRAG1\/IQSEC2 and its requirement in long-term depression","volume":"7","author":"Brown","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_9","unstructured":"(2023, June 05). IQSEC2-Related Disorder. Available online: https:\/\/rarechromo.org\/media\/information\/Chromosome_X\/IQSEC2-related%20disorder%20FTNW.pdf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/cge.13507","article-title":"Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype","volume":"95","author":"Radley","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/cge.13908","article-title":"IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?","volume":"99","author":"Lopergolo","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1038\/s41436-018-0327-7","article-title":"IQSEC2-related encephalopathy in males and females: A comparative study including 37 novel patients","volume":"21","author":"Mignot","year":"2019","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/humu.23670","article-title":"IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy","volume":"40","author":"Shoubridge","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103735","DOI":"10.1016\/j.ejmg.2019.103735","article-title":"Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene","volume":"63","author":"Barrie","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41588-018-0143-7","article-title":"De novo variants in neurodevelopmental disorders with epilepsy","volume":"50","author":"Heyne","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1092 human genomes","volume":"491","author":"Abecasis","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Baladron, B., Mielu, L.M., L\u00f3pez-Mart\u00edn, E., Barrero, M.J., Lopez, L., Alvarado, J.I., Monz\u00f3n, S., Varona, S., Cuesta, I., and Cazorla, R. (2022). Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169480"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10897-013-9671-6","article-title":"Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: Implications for genetic counseling and clinical diagnosis","volume":"23","author":"Gandomi","year":"2014","journal-title":"J. Genet. Couns."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ejhg.2013.113","article-title":"Expanding the phenotype of IQSEC2 mutations: Truncating mutations in severe intellectual disability","volume":"22","author":"Willems","year":"2014","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/ccr3.1139","article-title":"Developmental progression of intellectual disability, autism, and epilepsy in a child with an IQSEC2 gene mutation","volume":"5","author":"Zipper","year":"2017","journal-title":"Clin. Case Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s12041-020-01204-y","article-title":"Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder","volume":"99","author":"Accogli","year":"2020","journal-title":"J. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Levy, N.S., Borisov, V., Lache, O., and Levy, A.P. (2023). Molecular Insights into IQSEC2 Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054984"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","article-title":"The story of Rett syndrome: From clinic to neurobiology","volume":"56","author":"Chahrour","year":"2007","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Vidal, S., Xiol, C., Pascual-Alonso, A., O\u2019Callaghan, M., Pineda, M., and Armstrong, J. (2019). Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163925"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Spagnoli, C., Fusco, C., and Pisani, F. (2021). Rett Syndrome Spectrum in Monogenic Developmental-Epileptic Encephalopathies and Epilepsies: A Review. Genes, 12.","DOI":"10.3390\/genes12081157"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/humu.10194","article-title":"RettBASE: The IRSA MECP2 variation database-a new mutation database in evolution","volume":"21","author":"Christodoulou","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.12703\/r\/10-59","article-title":"Rett syndrome: Think outside the (skull) box","volume":"10","author":"Borloz","year":"2021","journal-title":"Fac. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/mrdd.10020","article-title":"Clinical manifestations and stages of Rett syndrome","volume":"8","author":"Hagberg","year":"2002","journal-title":"Ment. Retard. Dev. Disabil. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"For the RettSearch Consortium (Members listed in the Appendix), Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1002\/ajmg.a.38829","article-title":"Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices","volume":"176","author":"Boban","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kay, C., Leonard, H., Smith, J., Wong, K., and Downs, J. (2023). Genotype and sleep independently predict mental health in Rett syndrome: An observational study. J. Med. Genet.","DOI":"10.1136\/jmg-2022-108905"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0022-3476(94)70196-2","article-title":"Polysomnographic characteristics of patients with Rett syndrome","volume":"125","author":"Marcus","year":"1994","journal-title":"J. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11325-012-0654-x","article-title":"Polysomnographic findings in Rett syndrome: A case-control study","volume":"17","author":"Carotenuto","year":"2013","journal-title":"Sleep Breath."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ejpn.2018.09.003","article-title":"Polysomnographic findings in Rett syndrome","volume":"23","author":"Amaddeo","year":"2019","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1378\/chest.09-3021","article-title":"Unrecognized lung disease in classic Rett syndrome: A physiologic and high-resolution CT imaging study","volume":"138","author":"Guazzi","year":"2010","journal-title":"Chest"},{"key":"ref_37","first-page":"560120","article-title":"Inflammatory lung disease in Rett syndrome","volume":"2014","author":"Rossi","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"833239","DOI":"10.3389\/fneur.2022.833239","article-title":"Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers","volume":"13","author":"Leoncini","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1212\/01.wnl.0000304752.50773.ec","article-title":"Investigating genotype-phenotype relationships in Rett syndrome using an international data set","volume":"70","author":"Bebbington","year":"2008","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1136\/jmedgenet-2013-102113","article-title":"Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome","volume":"51","author":"Cuddapah","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e000731","DOI":"10.1136\/bmjpo-2020-000731","article-title":"Multisystem comorbidities in classic Rett syndrome: A scoping review","volume":"4","author":"Fu","year":"2020","journal-title":"BMJ Paediatr. Open"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.nbd.2015.05.005","article-title":"Unexpected cellular players in Rett syndrome pathology","volume":"92 Pt A","author":"Cronk","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1097\/MPG.0b013e31824b6159","article-title":"Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome","volume":"55","author":"Motil","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Frankel, E., Podder, A., Sharifi, M., Pillai, R., Belnap, N., Ramsey, K., Dodson, J., Venugopal, P., Brzezinski, M., and Llaci, L. (2023). Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders. Cells, 12.","DOI":"10.3390\/cells12101437"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gonzalez, J.N., Goldman, S., Carter, M.T., and Bain, J.M. (2023). Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder. Genes, 4.","DOI":"10.3390\/genes14061154"},{"key":"ref_46","unstructured":"(2023, April 01). Associazione AMA.le IQSEC2. Available online: https:\/\/amaleiqsec2.com\/."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/humu.23149","article-title":"Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes","volume":"38","author":"Parrini","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_49","unstructured":"(2023, June 05). ClinVar Tool, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/BF03344156","article-title":"Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr)","volume":"29","author":"Cacciari","year":"2006","journal-title":"J. Endocrinol. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1212\/WNL.0b013e31826e9a70","article-title":"Growth failure and outcome in Rett syndrome: Specific growth references","volume":"79","author":"Tarquinio","year":"2012","journal-title":"Neurology"},{"key":"ref_52","unstructured":"(2023, June 30). Rare Diseases: Signs and Symptoms. Available online: https:\/\/www.orpha.net\/consor\/cgi-bin\/Disease_HPOTerms.php?lng=EN."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1212\/01.wnl.0000291011.54508.aa","article-title":"Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome","volume":"70","author":"Neul","year":"2008","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/mds.870050303","article-title":"Rett syndrome and associated movement disorders","volume":"5","author":"FitzGerald","year":"1990","journal-title":"Mov. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/1469-7610.00236","article-title":"The Rett Syndrome Behaviour Questionnaire (RSBQ): Refining the behavioural phenotype of Rett syndrome","volume":"43","author":"Mount","year":"2002","journal-title":"J. Child. Psychol. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/MPG.0000000000002951","article-title":"Gastrointestinal Health Questionnaire for Rett Syndrome: Tool Development","volume":"72","author":"Motil","year":"2021","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"920","DOI":"10.3109\/00365529709011203","article-title":"Stool form scale as a useful guide to intestinal transit time","volume":"32","author":"Lewis","year":"1997","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1365-2869.1996.00251.x","article-title":"The Sleep Disturbance Scale for Children (SDSC): Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence","volume":"5","author":"Bruni","year":"1996","journal-title":"J. Sleep Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s11136-018-2057-3","article-title":"Psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) measure","volume":"28","author":"Downs","year":"2019","journal-title":"Qual. Life Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1111\/cch.12691","article-title":"Content validation of the Quality of Life Inventory-Disability","volume":"45","author":"Epstein","year":"2019","journal-title":"Child. Care Health Dev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e04222","DOI":"10.1016\/j.heliyon.2020.e04222","article-title":"The levelling-off of the secular trend of age at menarche among Italian girls","volume":"6","author":"Piras","year":"2020","journal-title":"Heliyon"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Roderick Little, J.A., and Donald Rubin, B. (2002). Statistical Analysis with Missing Data, John Wiley & Sons. [2nd ed.].","DOI":"10.1002\/9781119013563"},{"key":"ref_63","unstructured":"(2023, June 05). Italian Age Pyramid. Available online: https:\/\/www.tuttitalia.it\/statistiche\/popolazione-eta-sesso-stato-civile-2022\/."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"May, D., Kponee-Shovein, K., Mahendran, M., Downes, N., Sheng, K., Lefebvre, P., and Cheng, W.Y. (2023). Epidemiology and patient journey of Rett syndrome in the United States: A real-world evidence study. BMC Neurol., 23.","DOI":"10.1186\/s12883-023-03181-y"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13643-023-02169-6","article-title":"Global prevalence of Rett syndrome: Systematic review and meta-analysis","volume":"12","author":"Petriti","year":"2023","journal-title":"Syst. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s40168-016-0185-y","article-title":"Altered gut microbiota in Rett syndrome","volume":"4","author":"Strati","year":"2016","journal-title":"Microbiome"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e20160590","DOI":"10.1542\/peds.2016-0590","article-title":"Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants","volume":"137","author":"Tieder","year":"2016","journal-title":"Pediatrics"},{"key":"ref_68","unstructured":"(2023, July 05). National Demographic Indicators (Mother\u2019s Age at the First Childbirth). Available online: https:\/\/demo.istat.it\/tavole\/?t=indicatori&l=en."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/cge.13946","article-title":"De novo variants in neurodevelopmental disorders-experiences from a tertiary care center","volume":"100","author":"Brunet","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.fertnstert.2022.10.017","article-title":"The impact of paternal age on new mutations and disease in the next generation","volume":"118","author":"Wood","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_71","unstructured":"(2023, July 05). National Demographic Indicators (Father\u2019s Age at the First Childbirth). Available online: http:\/\/dati-giovani.istat.it\/Index.aspx?QueryId=10979#."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fnmol.2019.00043","article-title":"An IQSEC2 Mutation Associated with Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors","volume":"12","author":"Rogers","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e201900386","DOI":"10.26508\/lsa.201900386","article-title":"Heterozygous loss of function of IQSEC2\/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females","volume":"2","author":"Jackson","year":"2019","journal-title":"Life Sci. Alliance"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Levy, N.S., Umanah, G.K.E., Rogers, E.J., Jada, R., Lache, O., and Levy, A.P. (2019). IQSEC2-Associated Intellectual Disability and Autism. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123038"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"104758","DOI":"10.1016\/j.nbd.2020.104758","article-title":"Altered excitatory transmission onto hippocampal interneurons in the IQSEC2 mouse model of X-linked neurodevelopmental disease","volume":"137","author":"Sah","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_76","unstructured":"(2023, July 14). IQSEC2 and Pain Sensitivity. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=IQSEC2."},{"key":"ref_77","unstructured":"(2022, October 30). National Epidemiological Data on Breastfeeding (Istituto Superiore di Sanit\u00e0). Available online: https:\/\/www.epicentro.iss.it\/en\/breastfeeding\/epid-italy."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrneurol.2014.62","article-title":"The hidden genetics of epilepsy-a clinically important new paradigm","volume":"10","author":"Thomas","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S1474-4422(15)00250-1","article-title":"The genetic landscape of the epileptic encephalopathies of infancy and childhood","volume":"15","author":"McTague","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1684\/epd.2021.1244","article-title":"Developmental and epileptic encephalopathies: Recognition and approaches to care","volume":"23","author":"Raga","year":"2021","journal-title":"Epileptic Disord."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/epi.13381","article-title":"Primer Part 1-The building blocks of epilepsy genetics","volume":"57","author":"Helbig","year":"2016","journal-title":"Epilepsia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1038\/ejhg.2015.5","article-title":"Next-generation sequencing in X-linked intellectual disability","volume":"23","author":"Tzschach","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1002\/ajmg.a.38404","article-title":"The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey","volume":"173","author":"Helm","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrg2506","article-title":"Fundamental Concepts in Genetics: Genetics and the Understanding of Selection","volume":"10","author":"Hurst","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ejhg.2015.123","article-title":"Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders","volume":"24","author":"Moey","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nature24265","article-title":"Landscape of X chromosome inactivation across human tissues","volume":"550","author":"Tukiainen","year":"2017","journal-title":"Nature"},{"key":"ref_87","unstructured":"(2023, July 14). SMARCC1 Gene Description. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=SMARCC1."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.apnu.2018.02.002","article-title":"Cosleeping and Behavioral Sleep Problems in School-aged Children with Neurodevelopmental and Mental Health Disorders","volume":"32","author":"Meltzer","year":"2018","journal-title":"Arch. Psychiatr. Nurs."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/1866-1955-6-44","article-title":"The relationship between sleep and behavior in autism spectrum disorder (ASD): A review","volume":"6","author":"Cohen","year":"2014","journal-title":"J. Neurodev. Disord."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1122344","DOI":"10.3389\/fpsyt.2023.1122344","article-title":"A literature review of sleep problems and neurodevelopment disorders","volume":"14","year":"2023","journal-title":"Front. Psychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jpeds.2008.05.004","article-title":"Infant sleep location: Associated maternal and infant characteristics with sudden infant death syndrome prevention recommendations","volume":"153","author":"Fu","year":"2008","journal-title":"J. Pediatr."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1001\/jamapediatrics.2013.2560","article-title":"Trends and factors associated with infant bed sharing, 1993\u20132010: The National Infant Sleep Position Study","volume":"167","author":"Colson","year":"2013","journal-title":"JAMA Pediatr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s10578-006-0028-3","article-title":"Sleep disturbances and correlates of children with autism spectrum disorders","volume":"37","author":"Liu","year":"2006","journal-title":"Child. Psychiatry Hum. Dev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S2213-8587(22)00339-4","article-title":"Molecular basis of normal and pathological puberty: From basic mechanisms to clinical implications","volume":"11","author":"Argente","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3390\/endocrines3030035","article-title":"The Role of Genetics in Central Precocious Puberty: Confirmed and Potential Neuroendocrine Genetic and Epigenetic Contributors and Their Interactions with Endocrine Disrupting Chemicals (EDCs)","volume":"3","author":"Mucci","year":"2022","journal-title":"Endocrines"},{"key":"ref_96","unstructured":"(2023, July 14). IQSEC2 Gene Related Symptoms and Diseases. Available online: https:\/\/www.mendelian.co\/genes\/iqsec2."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.pediatrneurol.2014.08.013","article-title":"Pubertal development in Rett syndrome deviates from typical females","volume":"51","author":"Killian","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"104698","DOI":"10.1016\/j.isci.2022.104698","article-title":"Estimating the number of diseases\u2014The concept of rare, ultra-rare, and hyper-rare","volume":"25","author":"Smith","year":"2022","journal-title":"iScience"}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/9\/1442\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:09Z","timestamp":1760128689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/9\/1442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,24]]},"references-count":98,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["children10091442"],"URL":"https:\/\/doi.org\/10.3390\/children10091442","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,24]]}}}