{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T13:24:06Z","timestamp":1776259446856,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background:\u00a0TNRC6B encodes a core effector of the RNA-induced silencing complex and is essential for miRNA-mediated gene silencing. Pathogenic variants in TNRC6B have recently been associated with a neurodevelopmental disorder characterised by developmental delay, intellectual disability, and behavioural difficulties. Methods: We report a three-generation family with a 22q13.1 deletion encompassing only exons 2\u201323 of TNRC6B. Clinical data were collected from medical records and family interviews, and the findings were compared with those of published cohorts. Results: Affected individuals presented with developmental delay, speech and language impairment, autism spectrum disorder, ADHD, oppositional defiant disorder, craniosynostosis, joint laxity, clinodactyly, and cardiac valve anomalies. The father and paternal grandmother had learning difficulties and neurobehavioral features, while the proband exhibited a more severe phenotype. Conclusions: This report expands the phenotypic spectrum of TNRC6B-related neurodevelopmental disorder, highlighting craniosynostosis, joint and connective tissue features, and cardiac involvement. Our findings also underscore variable expressivity across generations and emphasise the relevance of both copy-number and sequence variants in TNRC6B in patients with neurodevelopmental disorders.<\/jats:p>","DOI":"10.3390\/genes17040464","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T12:25:30Z","timestamp":1776255930000},"page":"464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expansion of the Phenotypic Spectrum of TNRC6B-Related Neurodevelopmental Disorder in a Three-Generation Family with 22q13.1 Deletion"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2779-0968","authenticated-orcid":false,"given":"Jessica","family":"Archer","sequence":"first","affiliation":[{"name":"Hunter Genetics, New South Wales Health, Cnr. Turton Rd and Tinonee Rd., Waratah, NSW 2298, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2170-7265","authenticated-orcid":false,"given":"Sheridan","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Hunter Genetics, New South Wales Health, Cnr. Turton Rd and Tinonee Rd., Waratah, NSW 2298, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Buckman","sequence":"additional","affiliation":[{"name":"Tamworth Community Health Centre, Tamworth, NSW 2340, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Bain","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, New South Wales Health Pathology, John Hunter Hospital, New Lambton Heights, NSW 2305, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-6618","authenticated-orcid":false,"given":"Himanshu","family":"Goel","sequence":"additional","affiliation":[{"name":"Hunter Genetics, New South Wales Health, Cnr. Turton Rd and Tinonee Rd., Waratah, NSW 2298, Australia"},{"name":"School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R18","DOI":"10.1093\/hmg\/ddp072","article-title":"Small regulatory RNAs in neurodevelopmental disorders","volume":"18","author":"Chang","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Goel, H., and Goel, A. (2024). MicroRNA and Rare Human Diseases. Genes, 15.","DOI":"10.3390\/genes15101243"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1261\/rna.078709.121","article-title":"Impact of scaffolding protein TNRC6 paralogs on gene expression and splicing","volume":"27","author":"Johnson","year":"2021","journal-title":"RNA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/embor.2012.160","article-title":"Defining a new role of GW182 in maintaining miRNA stability","volume":"13","author":"Yao","year":"2012","journal-title":"EMBO Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1093\/nar\/gkq1099","article-title":"Divergent GW182 functional domains in the regulation of translational silencing","volume":"39","author":"Yao","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4144","DOI":"10.1128\/MCB.00380-09","article-title":"Functional dissection of the human TNRC6 (GW182-related) family of proteins","volume":"29","author":"Baillat","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1016\/j.cub.2005.10.048","article-title":"Identification of novel argonaute-associated proteins","volume":"15","author":"Meister","year":"2005","journal-title":"Curr. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum disorder","volume":"515","author":"Iossifov","year":"2014","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1136\/jmedgenet-2019-106470","article-title":"Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay\/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD","volume":"57","author":"Granadillo","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2408","DOI":"10.1002\/mgg3.2408","article-title":"Novel variants in TNRC6B cause global developmental delay with speech and behavioral abnormalities, short stature, low body weight, cafe-au-lait spots, and metabolic abnormality","volume":"12","author":"Yang","year":"2024","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00439-023-02636-z","article-title":"Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder","volume":"143","author":"Yahia","year":"2024","journal-title":"Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.seizure.2023.06.008","article-title":"Epilepsy and Autism spectrum disorder caused by a pathogenic variant in TNRC6B","volume":"110","year":"2023","journal-title":"Seizure"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/s41380-018-0020-x","article-title":"A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development","volume":"24","author":"Eising","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1136\/jmedgenet-2014-102582","article-title":"De novo and rare inherited mutations implicate the transcriptional coregulator TCF20\/SPBP in autism spectrum disorder","volume":"11","author":"Babbs","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.ajhg.2021.08.009","article-title":"High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population","volume":"108","author":"Mitani","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2521","DOI":"10.1002\/bdr2.2521","article-title":"A Case Report: Co-Occurrence of TNRC6B Gene Variant and Xq28 Microdeletion Syndrome With Comprehensive Literature Review","volume":"117","author":"Deng","year":"2025","journal-title":"Birth Defects Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Huang, Z.X., Chen, Y., Guo, H.R., and Chen, G.F. (2021). Systematic Review and Bioinformatic Analysis of microRNA Expression in Autism Spectrum Disorder Identifies Pathways Associated With Cancer, Metabolism, Cell Signaling, and Cell Adhesion. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.630876"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Harvey, D.C., Verma, R., Sedaghat, B., Hjelm, B.E., Morton, S.U., Seidman, J.G., and Kumar, S.R. (2023). Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1249605"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s11033-024-09835-5","article-title":"Identification of the synonymous variant c.3141G > A in TNRC6B gene that altered RNA splicing by minigene assay","volume":"51","author":"Zhou","year":"2024","journal-title":"Mol. Biol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/ajmg.a.63089","article-title":"Complex congenital cardiovascular anomaly in a patient with AGO1-associated disorder","volume":"191","author":"Takagi","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/cge.14114","article-title":"De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype","volume":"101","author":"Niu","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5797","DOI":"10.1038\/s41467-020-19572-5","article-title":"Germline AGO2 mutations impair RNA interference and human neurological development","volume":"11","author":"Lessel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41588-018-0067-2","article-title":"Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy","volume":"50","author":"Ishiura","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nrg3965","article-title":"Towards a molecular understanding of microRNA-mediated gene silencing","volume":"7","author":"Jonas","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.molcel.2011.09.007","article-title":"GW182 proteins directly recruit cytoplasmic deadenylase complexes to miRNA targets","volume":"1","author":"Braun","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1038\/s41467-024-46703-z","article-title":"Extended stop codon context predicts nonsense codon readthrough efficiency in human cells","volume":"15","author":"Mangkalaphiban","year":"2024","journal-title":"Nat. Commun."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/464\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T12:30:00Z","timestamp":1776256200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/464"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":26,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040464"],"URL":"https:\/\/doi.org\/10.3390\/genes17040464","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]}}}