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https://hdl.handle.net/2440/127150
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dc.contributor.author | Hildebrand, M.S. | - |
dc.contributor.author | Jackson, V.E. | - |
dc.contributor.author | Scerri, T.S. | - |
dc.contributor.author | Van Reyk, O. | - |
dc.contributor.author | Coleman, M. | - |
dc.contributor.author | Braden, R.O. | - |
dc.contributor.author | Turner, S. | - |
dc.contributor.author | Rigbye, K.A. | - |
dc.contributor.author | Boys, A. | - |
dc.contributor.author | Barton, S. | - |
dc.contributor.author | Webster, R. | - |
dc.contributor.author | Fahey, M. | - |
dc.contributor.author | Saunders, K. | - |
dc.contributor.author | Parry-Fielder, B. | - |
dc.contributor.author | Paxton, G. | - |
dc.contributor.author | Hayman, M. | - |
dc.contributor.author | Coman, D. | - |
dc.contributor.author | Goel, H. | - |
dc.contributor.author | Baxter, A. | - |
dc.contributor.author | Ma, A. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Neurology, 2020; 94(20):e2148-e2167 | - |
dc.identifier.issn | 0028-3878 | - |
dc.identifier.issn | 1526-632X | - |
dc.identifier.uri | http://hdl.handle.net/2440/127150 | - |
dc.description.abstract | OBJECTIVE:Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS:Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS:Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION:We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches. | - |
dc.description.statementofresponsibility | Michael S. Hildebrand, Victoria E. Jackson, Thomas S. Scerri, Olivia Van Reyk, Matthew Coleman ... Josef Gecz ... et al. | - |
dc.language.iso | en | - |
dc.publisher | American Academy of Neurology | - |
dc.rights | © 2020 American Academy of Neurology | - |
dc.source.uri | http://dx.doi.org/10.1212/wnl.0000000000009441 | - |
dc.subject | Apraxia; all clinical neurology; all pediatric; all genetics; developmental disorders | - |
dc.title | Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1212/wnl.0000000000009441 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1127144 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1063799 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1153614 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1006110 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1102971 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1105008 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Gecz, J. [0000-0002-7884-6861] | - |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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