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Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language\/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and\/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.<\/jats:p>","DOI":"10.1155\/2024\/9692863","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T17:20:24Z","timestamp":1711646424000},"page":"1-14","source":"Crossref","is-referenced-by-count":6,"title":["Genome Sequencing of Idiopathic Speech Delay"],"prefix":"10.1155","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-1260","authenticated-orcid":true,"given":"Else","family":"Eising","sequence":"first","affiliation":[{"name":"Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Vino","sequence":"additional","affiliation":[{"name":"Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Mabie","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Campbell","sequence":"additional","affiliation":[{"name":"School of Behavioral and Brain Sciences, Callier Center for Communication Disorders, University of Texas at Dallas, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence D.","family":"Shriberg","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-1996","authenticated-orcid":true,"given":"Simon E.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1080\/02699206.2019.1595732"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.3109\/02699206.2010.503006"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1044\/1092-4388(2002\/093)"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1044\/jslhr.4206.1461"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1991.tb14795.x"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-120213-092236"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2202764119"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01192-y"},{"key":"9","article-title":"Genomic contributions to infant and toddler vocabulary scores: implications for association with health-, cognition-, and behaviour-related outcomes","volume-title":"bioRxiv","author":"E. 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