{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:40:47Z","timestamp":1766050847464,"version":"3.41.2"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Phelan-McDermid syndrome (PMS) is a genetic disorder caused by the loss of the terminal region of chromosome 22 or by pathogenic or likely-pathogenic variants in <jats:italic>SHANK3<\/jats:italic> gene. Individuals with PMS are affected by a variable degree of intellectual disability, delay or absence of speech, low muscle tone, motor delay epilepsy, and autistic features. We have performed an observational trial aimed to psychometrically characterize individuals carrying deletions or pathogenic variants in <jats:italic>SHANK3<\/jats:italic>, to eventually build a foundation for a subsequent precision psychiatry clinical trial with vafidemstat, a LSD1 inhibitor in Phase II clinical development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We have conducted a pilot study to clinically characterize the profile of 30 subjects, all diagnosed of molecularly confirmed PMS. Subjects were phenotypically characterized by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). Nineteen patients were included in the pilot study, followed by additional 11 individuals in the validation set.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Unsupervised hierarchical clustering of the collected psychometric data identifies three groups of patients, with different cognitive and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be positively correlated with ADOS and negatively correlated with Vineland-A and -C scores. No correlation was detected between deletion size and the BPI and RBQ scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This analysis presents new data on the best potential endpoints, for a future clinical study exploring vafidemstat actionability for <jats:italic>SHANK3<\/jats:italic>-associated psychiatric disorders, constituting a good example of how Precision Medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2025.1511962","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T07:10:50Z","timestamp":1741072250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Phenotype and psychometric characterization of Phelan-McDermid syndrome patients: pioneering towards personalized medicine"],"prefix":"10.3389","volume":"16","author":[{"given":"Juli\u00e1n","family":"Nevado","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Ciceri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Bel-Fenell\u00f3s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jair A.","family":"Tenorio-Casta\u00f1o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Maes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Xaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Buesa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s13023-022-02180-5","article-title":"Phelan-McDermid syndrome: a classification system after 30 years of experience","volume":"17","author":"Phelan","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"B2","article-title":"Phelan-McDermid Syndrome","volume-title":"GeneReviews","author":"Phelan","year":"2024"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80809-0","article-title":"Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor\/PSD-95\/GKAP complex and cortactin","volume":"23","author":"Naisbitt","year":"1999","journal-title":"Neuron"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00931.x","article-title":"ProSAP\/Shank proteins\u2014a family of higher order organizing molecules of the post- synaptic density with an emerging role in human neurological disease","volume":"81","author":"Boeckers","year":"2002","journal-title":"J Neurochem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.652454","article-title":"Variability in Phelan-McDermid syndrome in a cohort of 210 individuals","volume":"13","author":"Nevado","year":"2022","journal-title":"Front Genet"},{"key":"B6","first-page":"104754","article-title":"European Phelan-McDermid syndrome consortium; Hennekam RC","volume-title":"Eur J Med Genet","author":"Sch\u00f6n","year":"2023"},{"key":"B7","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/cge.v101.1","article-title":"Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures","volume":"101","author":"Jain","year":"2022","journal-title":"Clin Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/cge.v104.2","article-title":"Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals","volume":"104","author":"Moffitt","year":"2023","journal-title":"Clin Genet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ng1933","article-title":"Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders","volume":"39","author":"Durand","year":"2007","journal-title":"Nat Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/2040-2392-4-18","article-title":"Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency","volume":"4","author":"Soorya","year":"2013","journal-title":"Mol Autism"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004580","article-title":"Meta-analysis of SHANK Mutations in Autism Spectrum Disor- ders: a gradient of severity in cognitive impairments","volume":"10","author":"Leblond","year":"2014","journal-title":"PloS Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s13023-015-0323-9","article-title":"Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype-phenotype correlations","volume":"10","author":"Oberman","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13229-018-0205-9","article-title":"Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations","volume":"9","author":"De Rubeis","year":"2018","journal-title":"Mol Autism"},{"key":"B14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s11689-021-09370-5","article-title":"Characterisation of the clinical phenotype in Phelan-McDermid syndrome","volume":"13","author":"Burdeus-Olavarrieta","year":"2021","journal-title":"J Neurodev Disord"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.836807","article-title":"Understanding behavior in phelan-mcDermid syndrome","volume":"13","author":"Landlust","year":"2022","journal-title":"Front Psychiatry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"104770","DOI":"10.1016\/j.ejmg.2023.104770","article-title":"Consensus recommendations on mental health issues in Phelan-McDermid syndrome","volume":"66","author":"Van Balkom","year":"2023","journal-title":"Eur J Med Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"104726","DOI":"10.1016\/j.ejmg.2023.104726","article-title":"Consensus recommendations on altered sensory functioning in Phelan-McDermid syndrome","volume":"66","author":"Walinga","year":"2023","journal-title":"Eur J Med Genet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"104745","DOI":"10.1016\/j.ejmg.2023.104745","article-title":"Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome","volume":"66","author":"Burdeus-Olavarrieta","year":"2023","journal-title":"Eur J Med Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-018-0073-1","article-title":"Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism","volume":"43","author":"Ma","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0110-8","article-title":"Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition","volume":"21","author":"Qin","year":"2018","journal-title":"Nat Neurosci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/s41398-021-01233-w","article-title":"Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice","volume":"11","author":"Zhang","year":"2021","journal-title":"Transl Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01508-8","article-title":"Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models","volume":"27","author":"Rapanelli","year":"2022","journal-title":"Mol Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0233468","article-title":"Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations","volume":"15","author":"Maes","year":"2020","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1192\/j.eurpsy.2020.5.s170-s171","article-title":"Poster EPA. EPP0681. E-Poster Presentations","volume":"63","author":"Bullock","year":"","journal-title":"European Psychiat"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-021-00797-x","article-title":"First-in-human randomized trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of the KDM1A inhibitor vafidemstat","volume":"35","author":"Antonijoan","year":"2021","journal-title":"CNS Drugs"},{"article-title":"REIMAGINE-AD vafidemstat shows efficacy in Alzheimer-related agitation & aggression after 12 months\u201d, Poster ADPD","year":"2021","author":"Boada","key":"B26"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.nsa.2024.105120","article-title":"Final Results: PORTICO a double-blind, randomized placebo controlled, adaptive phase IIb trial to assess vafidemstat\u2019s efficacy in treating borderline personality disorder","author":"Ropacki","year":"2024","journal-title":"Poster ECNP"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.13800","article-title":"REIMAGINE: A CNS basket trial showing safety and efficacy of vafidemstat on aggression in different psychiatric disorders","author":"Ferrer","year":"2024"},{"key":"B29","article-title":"The Repetitive Behaviours Questionnaire (RBQ)","volume-title":"Manual for Administration and Scorer Interpretation","author":"Moss","year":"2008"},{"volume-title":"Vineland adaptive behavior scales, Third edition (Vineland-3)","year":"2016","author":"Sparrow","key":"B30"},{"key":"B31","article-title":"ADOS-2","volume-title":"Escala de Observaci\u00f3n para el Diagn\u00f3stico del Autismo-2 Manual (T Luque, adaptadora)","author":"Lord","year":"2015"},{"key":"B32","article-title":"Battelle developmental inventory. Allen, Tex: DLM; Traslation to Spanish: De la Cruz y Gonz\u00e1lez, 1996","volume-title":"Inventario 636 de Desarrollo Battelle","author":"Newborg","year":"1988"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1023\/A:1013299028321","article-title":"The Behavior Problems Inventory: An instrument for the assessment of self-injury, stereotyped behavior, and aggression\/destruction in individuals with developmental disabilities","volume":"31","author":"Rojahn","year":"2001","journal-title":"J Autism Dev Disord"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.3390\/genes14081628","article-title":"Cognitive-Behavioral profile in pediatric patients with syndrome 5p-: genotype-phenotype correlationships","volume":"14","author":"Bel-Fenell\u00f3s","year":"2023","journal-title":"Genes"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-84858-7","article-title":"The elements of statistical learning: hierarchical clustering","volume":"16","author":"Hastie","year":"2001","journal-title":"Stat Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.25.14863","article-title":"Cluster analysis and display of genome-wide expression patterns","volume":"95","author":"Eisen","year":"1998","journal-title":"Proc Natl Acad Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617717000418","article-title":"Neuropsychological clustering in bipolar and major depressive disorder","volume":"23","author":"Cotrena","year":"2017","journal-title":"J Int Neuropsychol Soc"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/wics.v2:4","article-title":"Principal component analysis","volume":"2","author":"Abdi","year":"2010","journal-title":"Wiley Interdiscip reviews: Comput statist"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.18.10101","article-title":"Singular value decomposition for genome-wide expression data processing and modeling","volume":"97","author":"Alter","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.15482","article-title":"Neurodevelopmental profile and stages of regression in Phelan-McDermid syndrome","volume":"65","author":"Dille","year":"2023","journal-title":"Dev Med Child Neurol"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2025.1511962\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T07:10:55Z","timestamp":1741072255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2025.1511962\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":40,"alternative-id":["10.3389\/fpsyt.2025.1511962"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2025.1511962","relation":{},"ISSN":["1664-0640"],"issn-type":[{"type":"electronic","value":"1664-0640"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"article-number":"1511962"}}