{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T15:41:15Z","timestamp":1775576475085,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We describe clinical details, including novel findings, of two further children with the newly defined <jats:italic>TLK2<\/jats:italic>\u2010related disorder. One patient was recruited to the Deciphering Developmental Delay (DDD) Study to identify underlying etiology of global developmental delay. The other was detected on whole\u2010exome sequencing as part of second line investigations following normal microarray. Both patients were found to have de novo heterozygous pathogenic <jats:italic>TLK2<\/jats:italic> variants. A novel c.6del p.(Glu3Lysfs*) loss\u2010of\u2010function frameshift variant was found in Patient 1. A c.1121+1G&gt;A splice\u2010donor variant was detected in Patient 2. <jats:italic>TLK2<\/jats:italic>\u2010related neurodevelopmental disorder is a specific syndrome that has been recently described. Global developmental delay, behavioral problems, gastrointestinal disorders, and typical facial dysmorphism are common features. Neuropsychiatric disorders, ophthalmic, musculoskeletal and cranial abnormalities, as well as short stature, have also all been described. The novel findings we describe include sleep disturbance, nondifferentiation of lateral semi\u2010circular canals (where asymmetric semi\u2010circular canals were a feature in the previous cohort), vesico\u2010ureteric reflux, and bilateral periauricular skin tags. Here, we report a novel <jats:italic>TLK2<\/jats:italic> variant and previously undescribed features of <jats:italic>TLK2<\/jats:italic>\u2010related disorder, to expand the clinical phenotype and provide further genotype\u2013phenotype correlation.<\/jats:p>","DOI":"10.1002\/ajmg.a.62580","type":"journal-article","created":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T17:12:00Z","timestamp":1637860320000},"page":"931-940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Report of two children with global developmental delay in association with de novo <scp><i>TLK2<\/i><\/scp> variant and literature review"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2349-2688","authenticated-orcid":false,"given":"Emily","family":"Woods","sequence":"first","affiliation":[{"name":"Sheffield Children's Hospital NHS Foundation Trust  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Spiller","sequence":"additional","affiliation":[{"name":"Sheffield Diagnostic Genetics Service Sheffield Children's NHS Foundation Trust  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1488-3695","authenticated-orcid":false,"given":"Meena","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Sheffield Clinical Genetics Service Sheffield Children's NHS Foundation Trust  Sheffield UK"},{"name":"Department of Oncology &amp; Metabolism University of Sheffield  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/pch\/pxy093"},{"key":"e_1_2_9_3_1","unstructured":"Ellard S. Baple E.L. CallawayA. Berry I. Forrester N. Turnbull C. Owens M. Eccles D.M. Abbs S. Scott R. Deans Z.C. Lester T. Campbell J. Newman W.G(2020).ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020.https:\/\/www.acgs.uk.com\/media\/11631\/uk-practice-guidelines-for-variant-classification-v4-01-2020.pdf"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg151"},{"key":"e_1_2_9_5_1","unstructured":"Khan I.andLeventhal B.L.(2021).StatPearls [Internet]. Developmental Delay ed. [online] TreasureIsland: StatPearls Publishing.https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK562231\/."},{"issue":"3","key":"e_1_2_9_6_1","first-page":"138","article-title":"22q11.2 microduplication: An enigmatic genetic disorder. 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