{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:17:07Z","timestamp":1770970627777,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tourette Syndrome (TS) is a neurodevelopmental disorder with a complex genetic architecture, involving both rare high-impact variants and polygenic contributions. While several risk genes have been identified by whole-exome sequencing (WES), the relationship between genetic variants and clinical phenotype in TS patients remains insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an explorative clinical exome-based study in a cohort of 80 children and adolescents with TS (mean age 12.8 years; male:female = 70:10). Variants were classified as potentially causative (PC-Vs), variants of uncertain significance (VUS), or non-causative (NC-Vs) according to ACMG guidelines for variant evaluation and curated databases. Clinical assessment included tic severity through Yale Global Tic Severity Scale (YGTSS), cognitive testing, dysmorphic features, comorbid conditions, EEG and brain MRI analyses. Group comparisons were statistically performed to evaluate associations between genetic findings and phenotypic features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Out of the 80 patients, 11 (13.7%) carried PC-Vs, 29 (36.3%) VUS, and 40 (50%) NC-Vs. Patients with PC-Vs exhibited significantly higher tic severity (mean YGTSS 28 \u00b1 8.2) and lower IQ (67.6 \u00b1 31.0) compared with VUS (YGTSS 24.2 \u00b1 7.7; IQ 90.8 \u00b1 23.1) and NC-Vs (YGTSS 18.5 \u00b1 7.0; IQ 86.4 \u00b1 20.3) (p &amp;lt; 0.05). Conversely, positive family history of tics was more frequent in the NC-V group (55%) than in PC-Vs (27.3%) or VUS (27.6%) (p = 0.044). Potential causative variants included\n                      <jats:italic>de novo<\/jats:italic>\n                      or inherited mutations in genes implicated in synaptic transmission (\n                      <jats:italic>PNKD<\/jats:italic>\n                      ,\n                      <jats:italic>SLC6A1<\/jats:italic>\n                      ), ion channels (\n                      <jats:italic>CACNA1D<\/jats:italic>\n                      ), chromatin remodeling (\n                      <jats:italic>BRPF1<\/jats:italic>\n                      ,\n                      <jats:italic>KMT2C<\/jats:italic>\n                      ,\n                      <jats:italic>SMARCA2<\/jats:italic>\n                      ), and pleiotropic neurodevelopmental pathways (\n                      <jats:italic>PTEN<\/jats:italic>\n                      ,\n                      <jats:italic>RERE<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a dual model of genetic susceptibility in TS, where rare, high-impact exomic variants may contribute to more severe tics, cognitive impairment, and syndromic presentations, whereas polygenic inheritance mostly occurs in familial and milder forms. Incorporating exome sequencing into diagnostic workflows may enhance etiological classification and inform precision-medicine strategies for TS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1744145","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T07:23:48Z","timestamp":1770967428000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic architecture and clinical features of Tourette syndrome in a child and adolescent cohort: an explorative clinical exome-based study"],"prefix":"10.3389","volume":"17","author":[{"given":"Federica","family":"Saia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Mirabella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Longhitano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoletta","family":"Maugeri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Barone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci15050426","article-title":"Epidemiology of tourette syndrome","volume":"15","author":"Yilmaz","year":"2025","journal-title":"Brain Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26089","article-title":"Population prevalence of Tourette syndrome: A systematic review and meta-analysis","volume":"30","author":"Scharf","year":"2015","journal-title":"Mov Disord"},{"key":"B3","doi-asserted-by":"publisher","first-page":"16097","DOI":"10.1038\/nrdp.2016.97","article-title":"Gilles de la Tourette syndrome","volume":"3","author":"Robertson","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci6040093","article-title":"Genetic contributions to Tourette syndrome: State of the art and future directions","volume":"6","author":"Pagliaroli","year":"2016","journal-title":"Brain Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00415-016-8335-1","article-title":"Environmental risk factors for tic disorders: A systematic review and meta-analysis","volume":"264","author":"Qi","year":"2017","journal-title":"J Neurol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1985.01790310065008","article-title":"A twin study of Tourette syndrome","volume":"42","author":"Price","year":"1985","journal-title":"Arch Gen Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2015.0627","article-title":"Familial risks of Tourette syndrome and chronic tic disorders: A population-based cohort study","volume":"72","author":"Mataix-Cols","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"B8","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.neuron.2018.03.015","article-title":"De novo sequence and copy number variants implicate novel genes in Tourette disorder","volume":"98","author":"Wang","year":"2018","journal-title":"Neuron"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq365","article-title":"Loss-of-function variants in the genomes of healthy humans","volume":"19","author":"MacArthur","year":"2010","journal-title":"Hum Mol Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature21062","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","year":"2017","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.170","article-title":"PNKD gene associated with Tourette disorder or tic disorder in a multiplex family","volume":"23","author":"Sun","year":"2018","journal-title":"Mol Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.11.015","article-title":"Mutations in BRPF1 cause intellectual disability with ptosis and facial dysmorphism","volume":"100","author":"Yan","year":"2017","journal-title":"Am J Hum Genet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"8077","DOI":"10.1038\/s41467-023-43776-0","article-title":"Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD","volume":"14","author":"Wang","year":"2023","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100947","article-title":"The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change","volume":"25","author":"Rehm","year":"2023","journal-title":"Genet Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/diseases12050090","article-title":"A review of the CACNA gene family: Its role in neurological disorders","volume":"12","author":"Szymanowicz","year":"2024","journal-title":"Diseases"},{"key":"B16","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s41583-021-00443-x","article-title":"The role of GABAergic signalling in neurodevelopmental disorders","volume":"22","author":"Tang","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8122088","article-title":"The Reeler mouse: A translational model of human neurological conditions, or simply a good tool for better understanding neurodevelopment","volume":"8","author":"Lossi","year":"2019","journal-title":"J Clin Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1060515","article-title":"Reelin signaling in neurodevelopmental disorders and neurodegenerative diseases","volume":"11","author":"Joly-Amado","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2217\/epi.15.1","article-title":"Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders","volume":"7","author":"Vallianatos","year":"2015","journal-title":"Epigenomics"},{"key":"B20","author":"Wechsler","year":"2003","journal-title":"Wechsler Intelligence Scale for Children\u2013Fourth Edition (WISC-IV)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/00004583-198907000-00015","article-title":"The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity","volume":"28","author":"Leckman","year":"1989","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp32411","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"405424","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. 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":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw971","article-title":"The ExAC browser: displaying reference data information from over 60\u2013000 exomes","volume":"45","author":"Karczewski","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki033","article-title":"Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders","volume":"33","author":"Hamosh","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD\u00ae): optimizing its use in a clinical diagnostic or research setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Hum Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat Methods"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat Methods"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.10.669566","article-title":"MutationAssessor in cBioPortal","author":"Su","year":"2025","journal-title":"bioRxiv"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1101\/gr.097857.109","article-title":"Detection of nonneutral substitution rates on mammalian phylogenies","volume":"20","author":"Pollard","year":"2010","journal-title":"Genome Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-020-02167-4","article-title":"Current management of tics and Tourette syndrome","volume":"127","author":"Billnitzer","year":"2020","journal-title":"J Neural Transm"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00787-020-01521-8","article-title":"European clinical guidelines for Tourette syndrome and other tic disorders\u2014Summary","volume":"30","author":"Szejko","year":"2021","journal-title":"Eur Child Adolesc Psychiatry"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.neuron.2017.05.015","article-title":"De novo coding variants are strongly associated with Tourette disorder","volume":"94","author":"Willsey","year":"2017","journal-title":"Neuron"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0741-4","article-title":"Genome-wide analyses of Tourette syndrome identify risk genes and pathways","volume":"25","author":"Zhao","year":"2020","journal-title":"Mol Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.11.013","article-title":"Histone lysine methylases and demethylases in the landscape of human developmental disorders","volume":"102","author":"Faundes","year":"2018","journal-title":"Am J Hum Genet"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2247-3","article-title":"Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism","volume":"580","author":"Satterstrom","year":"2020","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.06.015","article-title":"Deciphering Developmental Disorders Study. Mutations in SMARCA2 cause Nicolaides-Baraitser syndrome","volume":"93","author":"Santen","year":"2013","journal-title":"Am J Hum Genet"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.03.002","article-title":"De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions","volume":"98","author":"Fregeau","year":"2016","journal-title":"Am J Hum Genet"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx175","article-title":"New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy","volume":"26","author":"Pinggera","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.12.008","article-title":"De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies","volume":"104","author":"Platzer","year":"2019","journal-title":"Am J Hum Genet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1077","article-title":"Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis","volume":"44","author":"Wang","year":"2012","journal-title":"Nat Genet"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0389-y","article-title":"PTEN hamartoma tumor syndrome","volume":"17","author":"Yehia","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.04.007","article-title":"Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism","volume":"108","author":"Chopra","year":"2021","journal-title":"Am J Hum Genet"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13986","article-title":"Defining the phenotypic spectrum of SLC6A1 mutations","volume":"59","author":"Johannesen","year":"2018","journal-title":"Epilepsia"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1744145\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T07:23:49Z","timestamp":1770967429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1744145\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":51,"alternative-id":["10.3389\/fpsyt.2026.1744145"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1744145","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]},"article-number":"1744145"}}