Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation
AuthorHildebrand, MS; Jackson, VE; Scerri, TS; Van Reyk, O; Coleman, M; Braden, RO; Turner, S; Rigbye, KA; Boys, A; Barton, S; ...
PublisherLIPPINCOTT WILLIAMS & WILKINS
University of Melbourne Author/sConnelly, Alan; Scerri, Thomas; Hildebrand, Michael; Amor, David; Delatycki, Martin; Reilly, Sheena; Scheffer, Ingrid; Morgan, Angela; Bahlo, Melanie; Barton, Sarah; ...
AffiliationFlorey Department of Neuroscience and Mental Health
Medical Biology (W.E.H.I.)
Melbourne School of Population and Global Health
Audiology and Speech Pathology
Medicine (Austin & Northern Health)
Document TypeJournal Article
CitationsHildebrand, 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. ,... Morgan, A. T. (2020). Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. NEUROLOGY, 94 (20), pp.E2148-E2167. https://doi.org/10.1212/WNL.0000000000009441.
Access StatusAccess this item via the Open Access location
Open Access URLPublished version
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.
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- Florey Department of Neuroscience and Mental Health - Research Publications 
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