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From the Department of Medicine (M.S.H., M.C., K.A.R., I.E.S.), The University of Melbourne, Austin Health, Heidelberg; Population Health and Immunity Division (V.E.J., T.S.S., M.B.), The Walter and Eliza Hall Institute of Medical Research; Departments of Medical Biology (V.E.J., T.S.S., M.B.) and Audiology and Speech Pathology (R.O.B., A.T.M.) and Department of Paediatrics, The Royal Children's Hospital (B.P.-F., G.P., M.H., D.J.A., I.E.S.), The University of Melbourne; Speech and Language (O.V.R., R.O.B., S.T., S.B., S.R., A.T.M.), Murdoch Children's Research Institute (M.S.H., D.J.A., I.E.S.); Victorian Clinical Genetics Services (A. Boys, M.D.), Parkville, Victoria; Department of Neurology (R.W.) and Clinical Genetics (A.M.), The Children's Hospital Westmead; Department of Paediatrics (M.F., K.S.), Monash University; Monash Children's Hospital (K.S.), Clayton, Victoria; The Wesley Hospital (D.C.), Auchenflower, Queensland; Hunter Genetics (H.G., A. Baxter), John Hunter Hospital, New Lambton Heights; Melbourne Children's Clinic (N.D.), Victoria; Griffith University (S.R.), Mount Gravatt, Queensland, Australia; UCL Great Ormond Street Institute of Child Health (F.J.L.), London, UK; Florey Institute of Neuroscience and Mental Health (A.C., I.E.S.), Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Robinson Research Institute and Adelaide Medical School, University of Adelaide, South Australia; Language and Genetics Department (S.E.F.), Max Planck Institute for Psycholinguistics; and Donders Institute for Brain, Cognition and Behaviour (S.E.F.), Radboud University, Nijmegen, the Netherlands.
Published: May 2020
AI Article Synopsis
Article 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; , , , , , , , , , ) 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.
