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Title: Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.
Austin Authors: Hildebrand, Michael S ;Jackson, Victoria E;Scerri, Thomas S;Van Reyk, Olivia;Coleman, Matthew J;Braden, Ruth O;Turner, Samantha;Rigbye, Kristin A;Boys, Amber;Barton, Sarah;Webster, Richard;Fahey, Michael;Saunders, Kerryn;Parry-Fielder, Bronwyn;Paxton, Georgia;Hayman, Michael;Coman, David;Goel, Himanshu;Baxter, Anne;Ma, Alan;Davis, Noni;Reilly, Sheena;Delatycki, Martin;Liégeois, Frederique J;Connelly, Alan;Gecz, Jozef;Fisher, Simon E;Amor, David J;Scheffer, Ingrid E ;Bahlo, Melanie;Morgan, Angela T
Affiliation: Hunter Genetics, John Hunter Hospital, New Lambton Heights, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Australia
Departments of Medical Biology and Audiology and Speech Pathology and Department of Paediatrics, The Royal Children's Hospital, The University of Melbourne, Australia
Speech and Language, Murdoch Children's Research Institute, Victorian Clinical Genetics Services, Parkville, Victoria
Department of Neurology and Clinical Genetics, The Children's Hospital Westmead, Australia
Department of Paediatrics, Monash University, Australia
Monash Children's Hospital, Clayton, Victoria, Australia
The Wesley Hospital, Auchenflower, Queensland, Australia
Melbourne Children's Clinic, Victoria, Australia
Griffith University, Mount Gravatt, Queensland, Australia
UCL Great Ormond Street Institute of Child Health, London, UK
Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
South Australian Health and Medical Research Institute, Robinson Research Institute and Adelaide Medical School, University of Adelaide, South Australia, Australia
Language and Genetics Department, Max Planck Institute for Psycholinguistics
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: May-2020
Date: 2020-04-28
Publication information: Neurology 2020; 94(20): e2148-e2167
Abstract: 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). 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. 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. 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.
DOI: 10.1212/WNL.0000000000009441
ORCID: 0000-0002-9758-9784
Journal: Neurology
PubMed URL: 32345733
Type: Journal Article
Appears in Collections:Journal articles

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