{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:44:32Z","timestamp":1768567472246,"version":"3.49.0"},"posted":{"date-parts":[[2024,4,23]]},"group-title":"Genetic and Genomic Medicine","reference-count":56,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far.<\/jats:p>\n                <jats:p>Here, we performed an in-depth characterization of speech and language disorders in 52,143 individuals, reconstructing clinical histories using a large-scale data mining approach of the Electronic Medical Records (EMR) from an entire large paediatric healthcare network.<\/jats:p>\n                <jats:p>\n                  The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of twenty-six broad speech and language diagnoses. We used Natural Language Processing to assess to which degree clinical diagnosis in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be easily retrieved through ICD-10 diagnosis codes, while stuttering as a speech phenotype was only coded in 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and to a lesser degree with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our EMR analysis were\n                  <jats:italic>STXBP1<\/jats:italic>\n                  (\n                  <jats:italic>n<\/jats:italic>\n                  =21),\n                  <jats:italic>PTEN<\/jats:italic>\n                  (\n                  <jats:italic>n<\/jats:italic>\n                  =20), and\n                  <jats:italic>CACNA1A<\/jats:italic>\n                  (\n                  <jats:italic>n<\/jats:italic>\n                  =18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of\n                  <jats:italic>STXBP1<\/jats:italic>\n                  and aphasia (\n                  <jats:italic>P<\/jats:italic>\n                  =8.57 x 10\n                  <jats:sup>-7<\/jats:sup>\n                  , CI=18.62-130.39) and\n                  <jats:italic>MYO7A<\/jats:italic>\n                  with speech and language development delay due to hearing loss (\n                  <jats:italic>P<\/jats:italic>\n                  =1.24 x 10\n                  <jats:sup>-5<\/jats:sup>\n                  , CI=17.46-Inf). Finally, in a sub-cohort of 726 individuals with whole exome sequencing data, we identified an enrichment of rare variants in synaptic protein and neuronal receptor pathways and associations of\n                  <jats:italic>UQCRC1<\/jats:italic>\n                  with expressive aphasia and\n                  <jats:italic>WASHC4<\/jats:italic>\n                  with abnormality of speech or vocalization.\n                <\/jats:p>\n                <jats:p>In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.<\/jats:p>","DOI":"10.1101\/2024.04.23.24306192","type":"posted-content","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T18:55:15Z","timestamp":1713898515000},"source":"Crossref","is-referenced-by-count":2,"title":["The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7290-4939","authenticated-orcid":false,"given":"Jan","family":"Magielski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0834-0750","authenticated-orcid":false,"given":"Sarah M.","family":"Ruggiero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0205-0648","authenticated-orcid":false,"given":"Julie","family":"Xian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shridhar","family":"Parthasarathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Galer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiva","family":"Ganesan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Back","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jillian","family":"McKee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"McSalley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander K.","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Donaher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8486-0558","authenticated-orcid":false,"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"3","key":"2024042611502090000_2024.04.23.24306192v1.1","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/brain\/awab364","article-title":"Atypical development of Broca\u2019s area in a large family with inherited stuttering","volume":"145","year":"2022","journal-title":"Brain"},{"key":"2024042611502090000_2024.04.23.24306192v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy304"},{"issue":"5","key":"2024042611502090000_2024.04.23.24306192v1.3","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1093\/brain\/awab327","article-title":"Assessing the landscape of STXBP1- related disorders in 534 individuals","volume":"145","year":"2022","journal-title":"Brain"},{"issue":"4","key":"2024042611502090000_2024.04.23.24306192v1.4","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ejpn.2011.04.006","article-title":"Endophenotypes of FOXP2: dysfunction within the human articulatory network","volume":"15","year":"2011","journal-title":"European Journal of Paediatric Neurology"},{"issue":"12","key":"2024042611502090000_2024.04.23.24306192v1.5","doi-asserted-by":"crossref","first-page":"5086","DOI":"10.1093\/brain\/awad314","article-title":"Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40","volume":"146","year":"2023","journal-title":"Brain"},{"key":"2024042611502090000_2024.04.23.24306192v1.6","doi-asserted-by":"crossref","unstructured":"Morgan AT , Amor DJ , St John MD , Scheffer IE , Hildebrand MS . 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