{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T21:24:29Z","timestamp":1785533069613,"version":"3.56.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Research Centre Egypt"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Biallelic variants in the adenosine deaminase tRNA specific 3 <jats:italic>(ADAT3)<\/jats:italic> gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families with <jats:italic>ADAT3<\/jats:italic>-related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified three <jats:italic>ADAT3<\/jats:italic> variants, including the Saudi founder variant c.430G\u2009&gt;\u2009A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G\u2009&gt;\u2009A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G\u2009&gt;\u2009A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients with <jats:italic>ADAT3<\/jats:italic>-related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G\u2009&gt;\u2009A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.<\/jats:p>","DOI":"10.1038\/s41598-025-06857-2","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T08:27:44Z","timestamp":1751012864000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ADAT3-related neurodevelopmental disorder in 24 new patients with a high frequency of the p.Val144Met and a new founder variant"],"prefix":"10.1038","volume":"15","author":[{"given":"Karima","family":"Rafat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa F.","family":"Abdel-Aleem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasnaa M.","family":"Elbendary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud Y.","family":"Issa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona L.","family":"Essawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif F.","family":"Abdel-Ghafar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada M. H.","family":"Abdel-Salam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdel-Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"6857_CR1","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.molmed.2014.01.008","volume":"20","author":"AG Torres","year":"2014","unstructured":"Torres, A. G., Batlle, E. & de Pouplana, L. R. Role of tRNA modifications in human diseases. Trends Mol. Med. 20, 306\u2013314 (2014).","journal-title":"Trends Mol. Med."},{"key":"6857_CR2","doi-asserted-by":"publisher","first-page":"6529","DOI":"10.1093\/nar\/gkab436","volume":"49","author":"E Ramos-Morales","year":"2021","unstructured":"Ramos-Morales, E. et al. The structure of the mouse ADAT2\/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination. Nucleic Acids Res. 49, 6529\u20136548 (2021).","journal-title":"Nucleic Acids Res."},{"key":"6857_CR3","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.7150\/ijbs.80233","volume":"19","author":"W Cui","year":"2023","unstructured":"Cui, W. et al. tRNA modifications and modifying enzymes in disease, the potential therapeutic targets. Int. J. Biol. Sci. 19, 1146\u20131162 (2023).","journal-title":"Int. J. Biol. Sci."},{"key":"6857_CR4","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1136\/jmedgenet-2012-101378","volume":"50","author":"AM Alazami","year":"2013","unstructured":"Alazami, A. M. et al. Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus. J. Med. Genet. 50, 425\u2013430 (2013).","journal-title":"J. Med. Genet."},{"key":"6857_CR5","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1002\/ajmg.a.37578","volume":"170A","author":"AW El-Hattab","year":"2016","unstructured":"El-Hattab, A. W. et al. ADAT3-related intellectual disability: further delineation of the phenotype. Am. J. Med. Genet. A. 170A, 1142\u20131147 (2016).","journal-title":"Am. J. Med. Genet. A"},{"key":"6857_CR6","first-page":"e19833","volume":"13","author":"W AlDhalaan","year":"2021","unstructured":"AlDhalaan, W., Syed, F., Javaid, H. A., AlSagheir, A. & Almustanyir, S. A rare case of adenosine deaminase tRNA-Specific 3 mutation, adrenal insufficiency, and rhabdomyolysis. Cureus 13, e19833 (2021).","journal-title":"Cureus"},{"key":"6857_CR7","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1261\/rna.076380.120","volume":"26","author":"J Ramos","year":"2020","unstructured":"Ramos, J. et al. Identification and rescue of a tRNA wobble inosine deficiency causing intellectual disability disorder. RNA 26, 1654\u20131666 (2020).","journal-title":"RNA"},{"key":"6857_CR8","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1002\/acn3.51506","volume":"9","author":"M Chopra","year":"2022","unstructured":"Chopra, M. et al. Mendelian etiologies identified with whole exome sequencing in cerebral palsy. Ann. Clin. Transl Neurol. 9, 193\u2013205 (2022).","journal-title":"Ann. Clin. Transl Neurol."},{"key":"6857_CR9","doi-asserted-by":"publisher","unstructured":"Hengel, H. et al. First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. Eur. J. Hum. Genet. 28 https:\/\/doi.org\/10.1038\/s41431-020-0609-9 (2020).","DOI":"10.1038\/s41431-020-0609-9"},{"key":"6857_CR10","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41439-018-0007-9","volume":"5","author":"AR Salehi Chaleshtori","year":"2018","unstructured":"Salehi Chaleshtori, A. R. et al. A novel 8-bp duplication in ADAT3 causes mild intellectual disability. Hum. Genome Var. 5, 7 (2018).","journal-title":"Hum. Genome Var."},{"key":"6857_CR11","doi-asserted-by":"publisher","first-page":"103549","DOI":"10.1016\/j.ejmg.2018.10.001","volume":"62","author":"R Sharkia","year":"2019","unstructured":"Sharkia, R. et al. A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome. Eur. J. Med. Genet. 62, 103549 (2019).","journal-title":"Eur. J. Med. Genet."},{"key":"6857_CR12","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1055\/s-0039-1693151","volume":"8","author":"E Thomas","year":"2019","unstructured":"Thomas, E. et al. Novel missense variants in ADAT3 as a cause of syndromic intellectual disability. J. Pediatr. Genet. 8, 244\u2013251 (2019).","journal-title":"J. Pediatr. Genet."},{"key":"6857_CR13","doi-asserted-by":"crossref","first-page":"e1038","DOI":"10.1002\/mgg3.1038","volume":"8","author":"A Yahia","year":"2020","unstructured":"Yahia, A. et al. Exome sequencing revealed mutations in ADAT3 and HERC2 genes in two Sudanese families with syndromic mental retardation. Mol. Genet. Genomic Med. 8, e1038 (2020).","journal-title":"Mol. Genet. Genomic Med."},{"key":"6857_CR14","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1177\/0734282905285244","volume":"24","author":"C DiStefano","year":"2006","unstructured":"DiStefano, C. & Dombrowski, S. C. Investigating the theoretical structure of the Stanford-Binet. J. Psychoeduc Assess. 24, 123\u2013136 (2006).","journal-title":"J. Psychoeduc Assess."},{"key":"6857_CR15","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","volume":"31","author":"PC Ng","year":"2003","unstructured":"Ng, P. C. & Henikoff, S. S. I. F. T. Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31, 3812\u20133814 (2003).","journal-title":"Nucleic Acids Res."},{"key":"6857_CR16","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1093\/bioinformatics\/btu703","volume":"31","author":"D Quang","year":"2014","unstructured":"Quang, D., Chen, Y. & Xie, X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 31, 761\u2013763 (2014).","journal-title":"Bioinformatics"},{"key":"6857_CR17","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/s41588-018-0329-z","volume":"51","author":"L Sundaram","year":"2019","unstructured":"Sundaram, L. et al. Author correction: predicting the clinical impact of human mutation with deep neural networks. Nat. Genet. 51, 364 (2019).","journal-title":"Nat. Genet."},{"key":"6857_CR18","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods. 7, 248\u2013249 (2010).","journal-title":"Nat. Methods"},{"key":"6857_CR19","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","volume":"11","author":"JM Schwarz","year":"2014","unstructured":"Schwarz, J. M. et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat. Methods. 11, 361\u2013362 (2014).","journal-title":"Nat. Methods"},{"key":"6857_CR20","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis, N. M. et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99, 877\u2013885 (2016).","journal-title":"Am. J. Hum. Genet."},{"key":"6857_CR21","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1002\/humu.23892","volume":"40","author":"L Wiel","year":"2019","unstructured":"Wiel, L. et al. MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum. Mutat. 40, 1030\u20131038 (2019).","journal-title":"Hum. Mutat."},{"key":"6857_CR22","doi-asserted-by":"publisher","first-page":"W306","DOI":"10.1093\/nar\/gki375","volume":"33","author":"E Capriotti","year":"2005","unstructured":"Capriotti, E., Fariselli, P. & Casadio, R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 33, W306\u2013W310 (2005).","journal-title":"Nucleic Acids Res."},{"key":"6857_CR23","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1002\/prot.20810","volume":"62","author":"J Cheng","year":"2006","unstructured":"Cheng, J., Randall, A. & Baldi, P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins 62, 1125\u20131132 (2006).","journal-title":"Proteins"},{"key":"6857_CR24","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/pro.3942","volume":"30","author":"CH Rodrigues","year":"2021","unstructured":"Rodrigues, C. H., Pires, D. E. & Ascher, D. B. DynaMut2: assessing changes in stability and flexibility upon single and multiple point missense mutations. Protein Sci. 30, 60\u201369 (2021).","journal-title":"Protein Sci."},{"key":"6857_CR25","doi-asserted-by":"publisher","first-page":"W140","DOI":"10.1093\/nar\/gkaa275","volume":"48","author":"D Wang","year":"2020","unstructured":"Wang, D. et al. MusiteDeep: a deep-learning based webserver for protein post-translational modification site prediction and visualization. Nucleic Acids Res. 48, W140\u2013W146 (2020).","journal-title":"Nucleic Acids Res."},{"key":"6857_CR26","doi-asserted-by":"crossref","unstructured":"Gruber, A. R., Bernhart, S. H. & Lorenz, R. The ViennaRNA web services. RNA Bioinformatics. 307\u2013326 (2015). (2015).","DOI":"10.1007\/978-1-4939-2291-8_19"},{"key":"6857_CR27","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.1038\/s41467-023-40909-3","volume":"14","author":"L AlAbdi","year":"2023","unstructured":"AlAbdi, L. et al. Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families. Nat. Commun. 14, 5269 (2023).","journal-title":"Nat. Commun."},{"key":"6857_CR28","doi-asserted-by":"publisher","first-page":"e00203","DOI":"10.1128\/MCB.00203-19","volume":"39","author":"J Ramos","year":"2019","unstructured":"Ramos, J. et al. Formation of tRNA wobble inosine in humans is disrupted by a millennia-old mutation causing intellectual disability. Mol. Cell. Biol. 39, e00203\u201300219 (2019).","journal-title":"Mol. Cell. Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-06857-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-06857-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-06857-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T21:03:29Z","timestamp":1751403809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-06857-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6857"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-06857-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,27]]},"assertion":[{"value":"2 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Helsinki\u2019s guiding principles were followed during the study conduct. The study has been approved by NRC Medical Research Ethics Committee of NRC and written informed consents were obtained from the parents.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20329"}}