{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:34:11Z","timestamp":1787747651346,"version":"build-2784847793"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["U54 HD061222"],"award-info":[{"award-number":["U54 HD061222"]}]},{"name":"National Institutes of Health","award":["P50HD103537"],"award-info":[{"award-number":["P50HD103537"]}]},{"name":"National Institutes of Health","award":["5T32MH065215"],"award-info":[{"award-number":["5T32MH065215"]}]},{"name":"International Rett Syndrome Foundation","award":["U54 HD061222"],"award-info":[{"award-number":["U54 HD061222"]}]},{"name":"International Rett Syndrome Foundation","award":["P50HD103537"],"award-info":[{"award-number":["P50HD103537"]}]},{"name":"International Rett Syndrome Foundation","award":["5T32MH065215"],"award-info":[{"award-number":["5T32MH065215"]}]},{"name":"Vanderbilt Postdoctoral Training Program in Functional Neurogenomics","award":["U54 HD061222"],"award-info":[{"award-number":["U54 HD061222"]}]},{"name":"Vanderbilt Postdoctoral Training Program in Functional Neurogenomics","award":["P50HD103537"],"award-info":[{"award-number":["P50HD103537"]}]},{"name":"Vanderbilt Postdoctoral Training Program in Functional Neurogenomics","award":["5T32MH065215"],"award-info":[{"award-number":["5T32MH065215"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing the MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age-dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity, allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.<\/jats:p>","DOI":"10.3390\/genes15050594","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T03:23:19Z","timestamp":1715138599000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Jonathan K.","family":"Merritt","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-7585","authenticated-orcid":false,"given":"Xiaolan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Henry Ford Health System, Detroit, MI 48202, USA"},{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond C.","family":"Caylor","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Skinner","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Friez","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan K.","family":"Percy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-5872","authenticated-orcid":false,"given":"Jeffrey L.","family":"Neul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett Syndrome: Revised Diagnostic Criteria and Nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s10354-016-0492-8","article-title":"On a Remarkable Syndrome of Cerebral Atrophy Associated with Hyperammonaemia in Childhood","volume":"166","author":"Rett","year":"2016","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_3","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_4","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_5","doi-asserted-by":"crossref","unstructured":"Abbas, A., Fayoud, A.M., El Din Moawad, M.H., Hamad, A.A., Hamouda, H., and Fouad, E.A. (2024). Safety and Efficacy of Trofinetide in Rett Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. BMC Pediatr., 24.","DOI":"10.1186\/s12887-024-04526-3"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/s41591-023-02398-1","article-title":"Trofinetide for the Treatment of Rett Syndrome: A Randomized Phase 3 Study","volume":"29","author":"Neul","year":"2023","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.yebeh.2016.10.006","article-title":"Effectiveness and Tolerability of Antiepileptic Drugs in 104 Girls with Rett Syndrome","volume":"66","author":"Vignoli","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E75","DOI":"10.1097\/BSD.0000000000001381","article-title":"Scoliosis in RETT Syndrome: A National Referral Centre Experience","volume":"36","author":"Menachem","year":"2023","journal-title":"Clin. Spine Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e328","DOI":"10.1097\/MD.0000000000000328","article-title":"Experience of Gastrostomy Using a Quality Care Framework: The Example of Rett Syndrome","volume":"93","author":"Downs","year":"2014","journal-title":"Medicine"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1086\/302690","article-title":"Rett Syndrome and Beyond: Recurrent Spontaneous and Familial MECP2 Mutations at CpG Hotspots","volume":"65","author":"Wan","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1093\/hmg\/9.9.1377","article-title":"MECP2 Mutations Account for Most Cases of Typical Forms of Rett Syndrome","volume":"9","author":"Bienvenu","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1177\/08830738030180100801","article-title":"Clinical Variability in Rett Syndrome","volume":"18","author":"Naidu","year":"2003","journal-title":"J. Child Neurol."},{"key":"ref_15","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_16","first-page":"6956934","article-title":"Analysis of the Phenotypes in the Rett Networked Database","volume":"2019","author":"Frullanti","year":"2019","journal-title":"Int. J. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Romano, A., Lotan, M., and Fabio, R.A. (2023). A Severity Comparison between Italian and Israeli Rett Syndrome Cohorts. Diagnostics, 13.","DOI":"10.3390\/diagnostics13213390"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s12041-015-0574-1","article-title":"X-Chromosome Inactivation and Escape","volume":"94","author":"Disteche","year":"2015","journal-title":"J. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S147","DOI":"10.1016\/S0387-7604(01)00376-X","article-title":"Mutations in the Gene Encoding Methyl-CpG-Binding Protein 2 Cause Rett Syndrome","volume":"23","author":"Zoghbi","year":"2001","journal-title":"Brain Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1086\/320109","article-title":"MECP2 Mutations in Sporadic Cases of Rett Syndrome Are Almost Exclusively of Paternal Origin","volume":"68","author":"Trappe","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1177\/08830738040190070501","article-title":"Influence of MECP2 Gene Mutation and X-Chromosome Inactivation on the Rett Syndrome Phenotype","volume":"19","author":"Chae","year":"2004","journal-title":"J. Child Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/humu.10243","article-title":"Mutations and Polymorphisms in the Human Methyl CpG-Binding Protein MECP2","volume":"22","author":"Laccone","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1750-1172-6-58","article-title":"Two New Rett Syndrome Families and Review of the Literature: Expanding the Knowledge of MECP2 Frameshift Mutations","volume":"6","author":"Ravn","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/ajmg.b.32534","article-title":"Familial Cases and Male Cases with MECP2 Mutations","volume":"174","author":"Zhang","year":"2017","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1136\/jmg.2006.045260","article-title":"Correlation between Clinical Severity in Patients with Rett Syndrome with a p.R168X or p.T158M MECP2 Mutation, and the Direction and Degree of Skewing of X-Chromosome Inactivation","volume":"44","author":"Archer","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1917","DOI":"10.1002\/mgg3.1917","article-title":"Analysis of X-inactivation Status in a Rett Syndrome Natural History Study Cohort","volume":"10","author":"Fang","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11983","DOI":"10.1038\/s41598-019-48385-w","article-title":"X Chromosome Inactivation Does Not Necessarily Determine the Severity of the Phenotype in Rett Syndrome Patients","volume":"9","author":"Xiol","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/1531-8249(200005)47:5<670::AID-ANA20>3.0.CO;2-F","article-title":"Influence of Mutation Type and X Chromosome Inactivation on Rett Syndrome Phenotypes","volume":"47","author":"Amir","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41597-020-00794-7","article-title":"A Catalogue of 863 Rett-Syndrome-Causing MECP2 Mutations and Lessons Learned from Data Integration","volume":"8","author":"Ehrhart","year":"2021","journal-title":"Sci. Data"},{"key":"ref_30","first-page":"989","article-title":"Detection of New Paternal Dystrophin Gene Mutations in Isolated Cases of Dystrophinopathy in Females","volume":"54","author":"Pegoraro","year":"1994","journal-title":"Am. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"dmm048025","DOI":"10.1242\/dmm.048025","article-title":"Accessible Analysis of Longitudinal Data with Linear Mixed Effects Models","volume":"15","author":"Murphy","year":"2022","journal-title":"Dis. Model. Mech."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1176\/appi.ajp.157.2.163","article-title":"How Can We Learn About Developmental Processes From Cross-Sectional Studies, or Can We?","volume":"157","author":"Kraemer","year":"2000","journal-title":"Am. J. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1146\/annurev.psych.093008.100356","article-title":"The Disaggregation of Within-Person and Between-Person Effects in Longitudinal Models of Change","volume":"62","author":"Curran","year":"2011","journal-title":"Annu. Rev. Psychol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1177\/17456916211008407","article-title":"Connecting Theory to Methods in Longitudinal Research","volume":"17","author":"Hopwood","year":"2022","journal-title":"Perspect. Psychol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v072.i07","article-title":"The R Package JMbayes for Fitting Joint Models for Longitudinal and Time-to-Event Data Using MCMC","volume":"72","author":"Rizopoulos","year":"2016","journal-title":"J. Stat. Softw."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/ajmg.10557","article-title":"Balanced X Chromosome Inactivation Patterns in the Rett Syndrome Brain","volume":"111","author":"Shahbazian","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1177\/0883073809350722","article-title":"Analysis of the Parental Origin of De Novo MECP2 Mutations and X Chromosome Inactivation in 24 Sporadic Patients With Rett Syndrome in China","volume":"25","author":"Zhu","year":"2010","journal-title":"J. Child Neurol."},{"key":"ref_38","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_39","doi-asserted-by":"crossref","unstructured":"Sadhu, C., Lyons, C., Oh, J., Jagadeeswaran, I., Gray, S.J., and Sinnett, S.E. (2023). The Efficacy of a Human-Ready miniMECP2 Gene Therapy in a Pre-Clinical Model of Rett Syndrome. Genes, 15.","DOI":"10.3390\/genes15010031"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1016\/j.ymthe.2023.07.013","article-title":"Novel MECP2 Gene Therapy Is Effective in a Multicenter Study Using Two Mouse Models of Rett Syndrome and Is Safe in Non-Human Primates","volume":"31","author":"Powers","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8185","DOI":"10.1073\/pnas.1800931115","article-title":"Tsix-Mecp2 Female Mouse Model for Rett Syndrome Reveals That Low-Level MECP2 Expression Extends Life and Improves Neuromotor Function","volume":"115","author":"Carrette","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"E668","DOI":"10.1073\/pnas.1715124115","article-title":"A Mixed Modality Approach towards Xi Reactivation for Rett Syndrome and Other X-Linked Disorders","volume":"115","author":"Carrette","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7991","DOI":"10.1073\/pnas.1803792115","article-title":"Pharmacological Reactivation of Inactive X-Linked Mecp2 in Cerebral Cortical Neurons of Living Mice","volume":"115","author":"Przanowski","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1352\/1944-7558-125.6.493","article-title":"A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials","volume":"125","author":"Raspa","year":"2020","journal-title":"Am. J. Intellect. Dev. Disabil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1229553","DOI":"10.3389\/fped.2023.1229553","article-title":"A Review of the Rett Syndrome Behaviour Questionnaire and Its Utilization in the Assessment of Symptoms Associated with Rett Syndrome","volume":"11","author":"Percy","year":"2023","journal-title":"Front. Pediatr."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Raspa, M., Gwaltney, A., Bann, C., von Hehn, J., Benke, T.A., Marsh, E.D., Peters, S.U., Ananth, A., Percy, A.K., and Neul, J.L. (2024). Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS). J. Autism Dev. Disord.","DOI":"10.1007\/s10803-024-06238-0"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:41:24Z","timestamp":1760107284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,8]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["genes15050594"],"URL":"https:\/\/doi.org\/10.3390\/genes15050594","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,8]]}}}