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https://hdl.handle.net/2440/127150
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Type: | Journal article |
Title: | Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation |
Author: | Hildebrand, M.S. Jackson, V.E. Scerri, T.S. Van Reyk, O. Coleman, M. Braden, R.O. Turner, S. Rigbye, K.A. Boys, A. Barton, S. Webster, R. Fahey, M. Saunders, K. Parry-Fielder, B. Paxton, G. Hayman, M. Coman, D. Goel, H. Baxter, A. Ma, A. et al. |
Citation: | Neurology, 2020; 94(20):e2148-e2167 |
Publisher: | American Academy of Neurology |
Issue Date: | 2020 |
ISSN: | 0028-3878 1526-632X |
Statement of Responsibility: | Michael S. Hildebrand, Victoria E. Jackson, Thomas S. Scerri, Olivia Van Reyk, Matthew Coleman ... Josef Gecz ... et al. |
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. |
Keywords: | Apraxia; all clinical neurology; all pediatric; all genetics; developmental disorders |
Rights: | © 2020 American Academy of Neurology |
DOI: | 10.1212/wnl.0000000000009441 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1127144 http://purl.org/au-research/grants/nhmrc/1063799 http://purl.org/au-research/grants/nhmrc/1153614 http://purl.org/au-research/grants/nhmrc/1006110 http://purl.org/au-research/grants/nhmrc/1102971 http://purl.org/au-research/grants/nhmrc/1105008 |
Published version: | http://dx.doi.org/10.1212/wnl.0000000000009441 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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