{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:22:38Z","timestamp":1790018558130,"version":"4.0.1"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004189","name":"Max-Planck-Gesellschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VI.Veni.202.072"],"award-info":[{"award-number":["VI.Veni.202.072"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leibniz Wissenschaftscampus primate cognition"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Developmental stuttering is a common childhood condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead for de novo variants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant in\n                    <jats:italic>SPTBN1<\/jats:italic>\n                    as well as likely pathogenic variants in\n                    <jats:italic>PRPF8<\/jats:italic>\n                    ,\n                    <jats:italic>TRIO<\/jats:italic>\n                    , and\n                    <jats:italic>ZBTB7A<\/jats:italic>\n                    - four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering:\n                    <jats:italic>FLT3<\/jats:italic>\n                    and\n                    <jats:italic>IREB2<\/jats:italic>\n                    . We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03170-2","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T08:13:31Z","timestamp":1755677611000},"page":"104-115","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["De novo protein-coding gene variants in developmental stuttering"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-1260","authenticated-orcid":false,"given":"Else","family":"Eising","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1340-5437","authenticated-orcid":false,"given":"Ivana","family":"Dzinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Vino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lottie","family":"Stipdonk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Pavlov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-599X","authenticated-orcid":false,"given":"Juliane","family":"Winkelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2534-2480","authenticated-orcid":false,"given":"Martin","family":"Sommer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine J. P.","family":"Franken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7447-2252","authenticated-orcid":false,"given":"Konrad","family":"Oexle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-1996","authenticated-orcid":false,"given":"Simon E.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"3170_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jfludis.2012.11.002","volume":"38","author":"E Yairi","year":"2013","unstructured":"Yairi E, Ambrose N. Epidemiology of stuttering: 21st century advances. J Fluency Disord. 2013;38:66\u201387.","journal-title":"J Fluency Disord"},{"key":"3170_CR2","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1044\/jslhr.4205.1097","volume":"42","author":"E Yairi","year":"1999","unstructured":"Yairi E, Ambrose NG. Early childhood stuttering I: persistency and recovery rates. J Speech Lang Hear Res. 1999;42:1097\u2013112.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1080\/14417040500055060","volume":"7","author":"A Craig","year":"2005","unstructured":"Craig A, Tran Y. The epidemiology of stuttering: the need for reliable estimates of prevalence and anxiety levels over the lifespan. Am J Speech Lang Pathol. 2005;7:41\u20136.","journal-title":"Am J Speech Lang Pathol"},{"key":"3170_CR4","doi-asserted-by":"publisher","first-page":"4356","DOI":"10.1044\/2019_JSLHR-19-00137","volume":"62","author":"SE Tichenor","year":"2019","unstructured":"Tichenor SE, Yaruss JS. Stuttering as defined by adults who stutter. J Speech Lang Hear Res. 2019;62:4356\u201369.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR5","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1080\/09638288.2018.1555623","volume":"42","author":"A Connery","year":"2020","unstructured":"Connery A, McCurtin A, Robinson K. The lived experience of stuttering: a synthesis of qualitative studies with implications for rehabilitation. Disabil Rehabil. 2020;42:2232\u201342.","journal-title":"Disabil Rehabil"},{"key":"3170_CR6","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1002\/mgg3.276","volume":"5","author":"C Frigerio-Domingues","year":"2017","unstructured":"Frigerio-Domingues C, Drayna D. Genetic contributions to stuttering: the current evidence. Mol Genet Genomic Med. 2017;5:95\u2013102.","journal-title":"Mol Genet Genomic Med"},{"key":"3170_CR7","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1044\/1058-0360(2007\/021)","volume":"16","author":"K Dworzynski","year":"2007","unstructured":"Dworzynski K, Remington A, Rijsdijk F, Howell P, Plomin R. Genetic etiology in cases of recovered and persistent stuttering in an unselected, longitudinal sample of young twins. Am J Speech Lang Pathol. 2007;16:169\u201378.","journal-title":"Am J Speech Lang Pathol"},{"key":"3170_CR8","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1044\/1092-4388(2009\/08-0202)","volume":"53","author":"CE van Beijsterveldt","year":"2010","unstructured":"van Beijsterveldt CE, Felsenfeld S, Boomsma DI. Bivariate genetic analyses of stuttering and nonfluency in a large sample of 5-year-old twins. J Speech Lang Hear Res. 2010;53:609\u201319.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR9","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1056\/NEJMoa0902630","volume":"362","author":"C Kang","year":"2010","unstructured":"Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, et al. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med. 2010;362:677\u201385.","journal-title":"N Engl J Med"},{"key":"3170_CR10","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.ajhg.2015.10.007","volume":"97","author":"MH Raza","year":"2015","unstructured":"Raza MH, Mattera R, Morell R, Sainz E, Rahn R, Gutierrez J, et al. Association between rare variants in AP4E1, a component of intracellular trafficking, and persistent stuttering. Am J Hum Genet. 2015;97:715\u201325.","journal-title":"Am J Hum Genet"},{"key":"3170_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s41065-021-00211-y","volume":"158","author":"Y Sun","year":"2021","unstructured":"Sun Y, Gao Y, Zhou Y, Zhou Y, Zhang Y, Wang D, et al. IFNAR1 gene mutation may contribute to developmental stuttering in the Chinese population. Hereditas. 2021;158:46.","journal-title":"Hereditas"},{"key":"3170_CR12","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.3390\/genes13122299","volume":"13","author":"AU Rehman","year":"2022","unstructured":"Rehman AU, Hamid M, Khan SA, Eisa M, Ullah W, Rehman ZU, et al. The expansion of the spectrum in stuttering disorders to a novel ARMC gene family (ARMC3). Genes. 2022;13:2299.","journal-title":"Genes"},{"key":"3170_CR13","doi-asserted-by":"crossref","unstructured":"Frigerio Domingues CE, Raza MH, Han T-U, Barnes T, Shaw P, Sudre G, et al. Mutations in ZBTB20 in individuals with persistent stuttering. medRxiv. 2022. 2022.2011.2003.22281471:1\u201323.","DOI":"10.1101\/2022.11.03.22281471"},{"key":"3170_CR14","doi-asserted-by":"publisher","first-page":"5086","DOI":"10.1093\/brain\/awad314","volume":"146","author":"AT Morgan","year":"2023","unstructured":"Morgan AT, Scerri TS, Vogel AP, Reid CA, Quach M, Jackson VE, et al. Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40. Brain. 2023;146:5086\u201397.","journal-title":"Brain"},{"key":"3170_CR15","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/ejhg.2015.154","volume":"24","author":"MH Raza","year":"2016","unstructured":"Raza MH, Domingues CE, Webster R, Sainz E, Paris E, Rahn R, et al. Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes. Eur J Hum Genet. 2016;24:529\u201334.","journal-title":"Eur J Hum Genet"},{"key":"3170_CR16","first-page":"100073","volume":"3","author":"HG Polikowsky","year":"2022","unstructured":"Polikowsky HG, Shaw DM, Petty LE, Chen HH, Pruett DG, Linklater JP, et al. Population-based genetic effects for developmental stuttering. HGG Adv. 2022;3:100073.","journal-title":"HGG Adv"},{"key":"3170_CR17","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1016\/j.ajhg.2021.11.004","volume":"108","author":"DM Shaw","year":"2021","unstructured":"Shaw DM, Polikowsky HP, Pruett DG, Chen HH, Petty LE, Viljoen KZ, et al. Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering. Am J Hum Genet. 2021;108:2271\u201383.","journal-title":"Am J Hum Genet"},{"key":"3170_CR18","doi-asserted-by":"crossref","unstructured":"Polikowsky HG, Scartozzi AC, Shaw DM, Pruett DG, Chen HH, Petty LE, et al. Large-scale genome-wide analyses of stuttering. Nat Genet 2025;57:1835\u201347.","DOI":"10.1038\/s41588-025-02267-2"},{"key":"3170_CR19","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.ymgme.2011.12.012","volume":"105","author":"MF Coutinho","year":"2012","unstructured":"Coutinho MF, Prata MJ, Alves S. Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol Genet Metab. 2012;105:542\u201350.","journal-title":"Mol Genet Metab"},{"key":"3170_CR20","doi-asserted-by":"publisher","first-page":"8259","DOI":"10.1080\/21655979.2021.1982846","volume":"12","author":"J Shin","year":"2021","unstructured":"Shin J, Nile A, Oh JW. Role of adaptin protein complexes in intracellular trafficking and their impact on diseases. Bioengineered. 2021;12:8259\u201378.","journal-title":"Bioengineered"},{"key":"3170_CR21","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","volume":"14","author":"LB Ivashkiv","year":"2014","unstructured":"Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36\u201349.","journal-title":"Nat Rev Immunol"},{"key":"3170_CR22","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S0962-8924(03)00167-3","volume":"13","author":"JC Coates","year":"2003","unstructured":"Coates JC. Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol. 2003;13:463\u201371.","journal-title":"Trends Cell Biol"},{"key":"3170_CR23","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1128\/MCB.01667-08","volume":"29","author":"AP Sutherland","year":"2009","unstructured":"Sutherland AP, Zhang H, Zhang Y, Michaud M, Xie Z, Patti ME, et al. Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. Mol Cell Biol. 2009;29:2804\u201315.","journal-title":"Mol Cell Biol"},{"key":"3170_CR24","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1126\/science.274.5293.1718","volume":"274","author":"BC Freeman","year":"1996","unstructured":"Freeman BC, Toft DO, Morimoto RI. Molecular chaperone machines: chaperone activities of the cyclophilin Cyp-40 and the steroid aporeceptor-associated protein p23. Science. 1996;274:1718\u201320.","journal-title":"Science"},{"key":"3170_CR25","doi-asserted-by":"publisher","first-page":"17515","DOI":"10.1073\/pnas.1901480116","volume":"116","author":"TU Han","year":"2019","unstructured":"Han TU, Root J, Reyes LD, Huchinson EB, Hoffmann JD, Lee WS, et al. Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum. Proc Natl Acad Sci USA. 2019;116:17515\u201324.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3170_CR26","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1002\/ajmg.a.32193","volume":"146A","author":"SS Cathey","year":"2008","unstructured":"Cathey SS, Kudo M, Tiede S, Raas-Rothschild A, Braulke T, Beck M, et al. Molecular order in mucolipidosis II and III nomenclature. Am J Med Genet A. 2008;146A:512\u20133.","journal-title":"Am J Med Genet A"},{"key":"3170_CR27","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1136\/jmg.2009.067736","volume":"47","author":"SS Cathey","year":"2010","unstructured":"Cathey SS, Leroy JG, Wood T, Eaves K, Simensen RJ, Kudo M, et al. Phenotype and genotype in mucolipidoses II and III alpha\/beta: a study of 61 probands. J Med Genet. 2010;47:38\u201348.","journal-title":"J Med Genet"},{"key":"3170_CR28","first-page":"2929","volume":"143","author":"D Ebrahimi-Fakhari","year":"2020","unstructured":"Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D\u2019Amore A, Eberhardt K, et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020;143:2929\u201344.","journal-title":"Brain"},{"key":"3170_CR29","doi-asserted-by":"crossref","unstructured":"Hernandez N, Bucciol G, Moens L, Le Pen J, Shahrooei M, Goudouris E, et al. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J Exp Med. 2019;216:2057\u201370.","DOI":"10.1084\/jem.20182295"},{"key":"3170_CR30","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1111\/cge.13749","volume":"97","author":"D Melis","year":"2020","unstructured":"Melis D, Carvalho D, Barbaro-Dieber T, Espay AJ, Gambello MJ, Gener B, et al. Primrose syndrome: characterization of the phenotype in 42 patients. Clin Genet. 2020;97:890\u2013901.","journal-title":"Clin Genet"},{"key":"3170_CR31","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1038\/s41380-024-02409-8","volume":"29","author":"AT Morgan","year":"2024","unstructured":"Morgan AT, Amor DJ, St John MD, Scheffer IE, Hildebrand MS. Genetic architecture of childhood speech disorder: a review. Mol Psychiatry. 2024;29:1281\u201392.","journal-title":"Mol Psychiatry"},{"key":"3170_CR32","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1038\/s41380-018-0020-x","volume":"24","author":"E Eising","year":"2019","unstructured":"Eising E, Carrion-Castillo A, Vino A, Strand EA, Jakielski KJ, Scerri TS, et al. A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Mol Psychiatry. 2019;24:1065\u201378.","journal-title":"Mol Psychiatry"},{"key":"3170_CR33","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1038\/s41380-022-01879-y","volume":"28","author":"A Kaspi","year":"2023","unstructured":"Kaspi A, Hildebrand MS, Jackson VE, Braden R, van Reyk O, Howell T, et al. Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development. Mol Psychiatry. 2023;28:1647\u201363.","journal-title":"Mol Psychiatry"},{"key":"3170_CR34","doi-asserted-by":"publisher","first-page":"9692863","DOI":"10.1155\/2024\/9692863","volume":"2024","author":"E Eising","year":"2024","unstructured":"Eising E, Vino A, Mabie HL, Campbell TF, Shriberg LD, Fisher SE. Genome sequencing of idiopathic speech delay. Hum Mutat. 2024;2024:9692863.","journal-title":"Hum Mutat"},{"key":"3170_CR35","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nature21062","volume":"542","author":"Deciphering Developmental Disorders S","year":"2017","unstructured":"Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433\u20138.","journal-title":"Nature"},{"key":"3170_CR36","doi-asserted-by":"publisher","first-page":"e2148","DOI":"10.1212\/WNL.0000000000009441","volume":"94","author":"MS Hildebrand","year":"2020","unstructured":"Hildebrand MS, Jackson VE, Scerri TS, Van Reyk O, Coleman M, Braden RO, et al. Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation. Neurology. 2020;94:e2148\u2013e2167.","journal-title":"Neurology"},{"key":"3170_CR37","doi-asserted-by":"publisher","first-page":"1396240","DOI":"10.3389\/fnins.2024.1396240","volume":"18","author":"D Formicola","year":"2024","unstructured":"Formicola D, Podda I, Dirupo E, Andreucci E, Giglio S, Cipriani P, et al. Expanding the molecular landscape of childhood apraxia of speech: evidence from a single-center experience. Front Neurosci. 2024;18:1396240.","journal-title":"Front Neurosci"},{"key":"3170_CR38","doi-asserted-by":"publisher","first-page":"e0133758","DOI":"10.1371\/journal.pone.0133758","volume":"10","author":"C de Sonneville-Koedoot","year":"2015","unstructured":"de Sonneville-Koedoot C, Stolk E, Rietveld T, Franken MC. Direct versus indirect treatment for preschool children who stutter: the RESTART randomized trial. PLoS ONE. 2015;10:e0133758.","journal-title":"PLoS ONE"},{"key":"3170_CR39","volume-title":"The stuttering severity instrument for adults and children (SSI-4)","author":"G Riley","year":"2009","unstructured":"Riley G. The stuttering severity instrument for adults and children (SSI-4). 4th Edn. Austin. TX: PRO-ED; 2009.","edition":"4th Edn"},{"key":"3170_CR40","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1044\/2024_JSLHR-23-00562","volume":"67","author":"MM Engelen","year":"2024","unstructured":"Engelen MM, Franken MJP, Stipdonk LW, Horton SE, Jackson VE, Reilly S, et al. The association between stuttering burden and psychosocial aspects of life in adults. J Speech Lang Hear Res. 2024;67:1385\u201399.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR41","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/S1474-4422(20)30312-4","volume":"19","author":"M Zech","year":"2020","unstructured":"Zech M, Jech R, Boesch S, Skorvanek M, Weber S, Wagner M, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 2020;19:908\u201318.","journal-title":"Lancet Neurol"},{"key":"3170_CR42","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343.","journal-title":"Nature"},{"key":"3170_CR43","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","volume":"45","author":"GT Consortium","year":"2013","unstructured":"Consortium GT. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580\u20135.","journal-title":"Nat Genet"},{"key":"3170_CR44","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.","journal-title":"Nucleic Acids Res"},{"key":"3170_CR45","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1038\/ng.3703","volume":"48","author":"KA Jagadeesh","year":"2016","unstructured":"Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016;48:1581\u20136.","journal-title":"Nat Genet"},{"key":"3170_CR46","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877\u201385.","journal-title":"Am J Hum Genet"},{"key":"3170_CR47","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1038\/s41588-018-0167-z","volume":"50","author":"L Sundaram","year":"2018","unstructured":"Sundaram L, Gao H, Padigepati SR, McRae JF, Li Y, Kosmicki JA, et al. Predicting the clinical impact of human mutation with deep neural networks. Nat Genet. 2018;50:1161\u201370.","journal-title":"Nat Genet"},{"key":"3170_CR48","doi-asserted-by":"publisher","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","volume":"381","author":"J Cheng","year":"2023","unstructured":"Cheng J, Novati G, Pan J, Bycroft C, Zemgulyte A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381:eadg7492.","journal-title":"Science"},{"key":"3170_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-024-03327-8","volume":"11","author":"H Tordai","year":"2024","unstructured":"Tordai H, Torres O, Csepi M, Padanyi R, Lukacs GL, Hegedus T. Analysis of AlphaMissense data in different protein groups and structural context. Sci Data. 2024;11:495.","journal-title":"Sci Data"},{"key":"3170_CR50","doi-asserted-by":"publisher","first-page":"e4582","DOI":"10.1002\/pro.4582","volume":"32","author":"B Yariv","year":"2023","unstructured":"Yariv B, Yariv E, Kessel A, Masrati G, Chorin AB, Martz E, et al. Using evolutionary data to make sense of macromolecules with a \u201cface-lifted\u201d ConSurf. Protein Sci. 2023;32:e4582.","journal-title":"Protein Sci"},{"key":"3170_CR51","doi-asserted-by":"publisher","first-page":"eaat7615","DOI":"10.1126\/science.aat7615","volume":"362","author":"M Li","year":"2018","unstructured":"Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018;362:eaat7615.","journal-title":"Science"},{"key":"3170_CR52","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1126\/science.aaa0355","volume":"348","author":"M Mele","year":"2015","unstructured":"Mele M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. Human genomics. The human transcriptome across tissues and individuals. Science. 2015;348:660\u20135.","journal-title":"Science"},{"key":"3170_CR53","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1093\/brain\/awae264","volume":"148","author":"JH Magielski","year":"2025","unstructured":"Magielski JH, Ruggiero SM, Xian J, Parthasarathy S, Galer PD, Ganesan S, et al. The clinical and genetic spectrum of paediatric speech and language disorders. Brain. 2025;148:663\u201374.","journal-title":"Brain"},{"key":"3170_CR54","unstructured":"denovo-db, Seattle, WA (denovo-db.gs.washington.edu) [May 2024]"},{"key":"3170_CR55","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1002\/aur.2236","volume":"12","author":"M Belmadani","year":"2019","unstructured":"Belmadani M, Jacobson M, Holmes N, Phan M, Nguyen T, Pavlidis P, et al. VariCarta: a comprehensive database of harmonized genomic variants found in autism spectrum disorder sequencing studies. Autism Res. 2019;12:1728\u201336.","journal-title":"Autism Res"},{"key":"3170_CR56","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"3170_CR57","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","volume":"9","author":"P Langfelder","year":"2008","unstructured":"Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.","journal-title":"BMC Bioinformatics"},{"key":"3170_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-48","volume":"10","author":"E Eden","year":"2009","unstructured":"Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48.","journal-title":"BMC Bioinformatics"},{"key":"3170_CR59","doi-asserted-by":"publisher","first-page":"e2401687121","DOI":"10.1073\/pnas.2401687121","volume":"121","author":"MMK Wong","year":"2024","unstructured":"Wong MMK, Sha Z, Lutje L, Kong XZ, van Heukelum S, van de Berg WDJ, et al. The neocortical infrastructure for language involves region-specific patterns of laminar gene expression. Proc Natl Acad Sci USA. 2024;121:e2401687121.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3170_CR60","doi-asserted-by":"publisher","first-page":"eadd2870","DOI":"10.1126\/sciadv.add2870","volume":"9","author":"Z Sha","year":"2023","unstructured":"Sha Z, Schijven D, Fisher SE, Francks C. Genetic architecture of the white matter connectome of the human brain. Sci Adv. 2023;9:eadd2870.","journal-title":"Sci Adv"},{"key":"3170_CR61","doi-asserted-by":"publisher","first-page":"D977","DOI":"10.1093\/nar\/gkac1010","volume":"51","author":"E Sollis","year":"2023","unstructured":"Sollis E, Mosaku A, Abid A, Buniello A, Cerezo M, Gil L, et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2023;51:D977\u2013D985.","journal-title":"Nucleic Acids Res"},{"key":"3170_CR62","doi-asserted-by":"publisher","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","volume":"11","author":"CA de Leeuw","year":"2015","unstructured":"de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.","journal-title":"PLoS Comput Biol"},{"key":"3170_CR63","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/s41588-021-00886-z","volume":"53","author":"MA Cousin","year":"2021","unstructured":"Cousin MA, Creighton BA, Breau KA, Spillmann RC, Torti E, Dontu S, et al. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat Genet. 2021;53:1006\u201321.","journal-title":"Nat Genet"},{"key":"3170_CR64","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1002\/ajmg.a.62201","volume":"185","author":"JA Rosenfeld","year":"2021","unstructured":"Rosenfeld JA, Xiao R, Bekheirnia MR, Kanani F, Parker MJ, Koenig MK, et al. Heterozygous variants in SPTBN1 cause intellectual disability and autism. Am J Med Genet A. 2021;185:2037\u201345.","journal-title":"Am J Med Genet A"},{"key":"3170_CR65","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.ajhg.2020.01.018","volume":"106","author":"S Barbosa","year":"2020","unstructured":"Barbosa S, Greville-Heygate S, Bonnet M, Godwin A, Fagotto-Kaufmann C, Kajava AV, et al. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am J Hum Genet. 2020;106:338\u201355.","journal-title":"Am J Hum Genet"},{"key":"3170_CR66","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/ajmg.a.62492","volume":"188","author":"C von der Lippe","year":"2022","unstructured":"von der Lippe C, Tveten K, Prescott TE, Holla OL, Busk OL, Burke KB, et al. Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin. Am J Med Genet A. 2022;188:272\u201382.","journal-title":"Am J Med Genet A"},{"key":"3170_CR67","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s10038-019-0690-5","volume":"65","author":"A Ohishi","year":"2020","unstructured":"Ohishi A, Masunaga Y, Iijima S, Yamoto K, Kato F, Fukami M, et al. De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions. J Hum Genet. 2020;65:181\u20136.","journal-title":"J Hum Genet"},{"key":"3170_CR68","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/s41436-019-0612-0","volume":"22","author":"K Weiss","year":"2020","unstructured":"Weiss K, Lazar HP, Kurolap A, Martinez AF, Paperna T, Cohen L, et al. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis. Genet Med. 2020;22:389\u201397.","journal-title":"Genet Med"},{"key":"3170_CR69","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1016\/j.cell.2013.10.031","volume":"155","author":"NN Parikshak","year":"2013","unstructured":"Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013;155:1008\u201321.","journal-title":"Cell"},{"key":"3170_CR70","doi-asserted-by":"publisher","first-page":"15686","DOI":"10.1073\/pnas.1820649116","volume":"116","author":"DN Lorenzo","year":"2019","unstructured":"Lorenzo DN, Badea A, Zhou R, Mohler PJ, Zhuang X, Bennett V. betaII-spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport. Proc Natl Acad Sci USA. 2019;116:15686\u201395.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3170_CR71","doi-asserted-by":"publisher","first-page":"2750","DOI":"10.1002\/ajmg.a.62772","volume":"188","author":"L O\u2019Grady","year":"2022","unstructured":"O\u2019Grady L, Schrier Vergano SA, Hoffman TL, Sarco D, Cherny S, Bryant E, et al. Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders. Am J Med Genet A. 2022;188:2750\u20139.","journal-title":"Am J Med Genet A"},{"key":"3170_CR72","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.molcel.2007.01.023","volume":"25","author":"V Pena","year":"2007","unstructured":"Pena V, Liu S, Bujnicki JM, Luhrmann R, Wahl MC. Structure of a multipartite protein-protein interaction domain in splicing factor prp8 and its link to retinitis pigmentosa. Mol Cell. 2007;25:615\u201324.","journal-title":"Mol Cell"},{"key":"3170_CR73","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1038\/s41380-023-01963-x","volume":"28","author":"M Bonnet","year":"2023","unstructured":"Bonnet M, Roche F, Fagotto-Kaufmann C, Gazdagh G, Truong I, Comunale F, et al. Pathogenic TRIO variants associated with neurodevelopmental disorders perturb the molecular regulation of TRIO and axon pathfinding in vivo. Mol Psychiatry. 2023;28:1527\u201344.","journal-title":"Mol Psychiatry"},{"key":"3170_CR74","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/1074-7613(95)90167-1","volume":"3","author":"K Mackarehtschian","year":"1995","unstructured":"Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2\/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3:147\u201361.","journal-title":"Immunity"},{"key":"3170_CR75","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/84859","volume":"27","author":"T LaVaute","year":"2001","unstructured":"LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209\u201314.","journal-title":"Nat Genet"},{"key":"3170_CR76","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1044\/jslhr.4003.567","volume":"40","author":"NG Ambrose","year":"1997","unstructured":"Ambrose NG, Cox NJ, Yairi E. The genetic basis of persistence and recovery in stuttering. J Speech Lang Hear Res. 1997;40:567\u201380.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR77","doi-asserted-by":"publisher","first-page":"2895","DOI":"10.1044\/2018_JSLHR-S-17-0378","volume":"61","author":"PM Briley","year":"2018","unstructured":"Briley PM, Ellis C Jr. The coexistence of disabling conditions in children who stutter: evidence from the national health interview survey. J Speech Lang Hear Res. 2018;61:2895\u2013905.","journal-title":"J Speech Lang Hear Res"},{"key":"3170_CR78","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1002\/ajmg.a.62899","volume":"188","author":"M St John","year":"2022","unstructured":"St John M, Amor DJ, Morgan AT. Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome. Am J Med Genet A. 2022;188:3389\u20133400.","journal-title":"Am J Med Genet A"},{"key":"3170_CR79","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/s41431-021-00894-x","volume":"29","author":"A Morgan","year":"2021","unstructured":"Morgan A, Braden R, Wong MMK, Colin E, Amor D, Liegeois F, et al. Speech and language deficits are central to SETBP1 haploinsufficiency disorder. Eur J Hum Genet. 2021;29:1216\u201325.","journal-title":"Eur J Hum Genet"},{"key":"3170_CR80","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2024.104923","volume":"68","author":"LD Morison","year":"2024","unstructured":"Morison LD, Van Reyk O, Baker E, Ruaud L, Couque N, Verloes A, et al. Beyond \u2018speech delay\u2019: expanding the phenotype of BRPF1-related disorder. Eur J Med Genet. 2024;68:104923.","journal-title":"Eur J Med Genet"},{"key":"3170_CR81","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41583-022-00674-6","volume":"24","author":"DN Lorenzo","year":"2023","unstructured":"Lorenzo DN, Edwards RJ, Slavutsky AL. Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci. 2023;24:195\u2013212.","journal-title":"Nat Rev Neurosci"},{"key":"3170_CR82","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1177\/1073858418803594","volume":"25","author":"SE Chang","year":"2019","unstructured":"Chang SE, Garnett EO, Etchell A, Chow HM. Functional and neuroanatomical bases of developmental stuttering: current insights. Neuroscientist. 2019;25:566\u201382.","journal-title":"Neuroscientist"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03170-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T12:02:48Z","timestamp":1765540968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03170-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,20]]},"references-count":82,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["3170"],"URL":"https:\/\/doi.org\/10.1038\/s41380-025-03170-2","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,20]]},"assertion":[{"value":"22 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}