Michael S Hildebrand1, Victoria E Jackson2, Thomas S Scerri2, Olivia Van Reyk2, Matthew Coleman2, Ruth O Braden2, Samantha Turner2, Kristin A Rigbye2, Amber Boys2, Sarah Barton2, Richard Webster2, Michael Fahey2, Kerryn Saunders2, Bronwyn Parry-Fielder2, Georgia Paxton2, Michael Hayman2, David Coman2, Himanshu Goel2, Anne Baxter2, Alan Ma2, Noni Davis2, Sheena Reilly2, Martin Delatycki2, Frederique J Liégeois2, Alan Connelly2, Jozef Gecz2, Simon E Fisher2, David J Amor2, Ingrid E Scheffer2, Melanie Bahlo2, Angela T Morgan1. 1. 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. michael.hildebrand@unimelb.edu.au angela.morgan@mcri.edu.au. 2. 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.
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.
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.
Authors: Antony Kaspi; Angela T Morgan; Michael S Hildebrand; Victoria E Jackson; Ruth Braden; Olivia van Reyk; Tegan Howell; Simone Debono; Mariana Lauretta; Lottie Morison; Matthew J Coleman; Richard Webster; David Coman; Himanshu Goel; Mathew Wallis; Gabriel Dabscheck; Lilian Downie; Emma K Baker; Bronwyn Parry-Fielder; Kirrie Ballard; Eva Harrold; Shaun Ziegenfusz; Mark F Bennett; Erandee Robertson; Longfei Wang; Amber Boys; Simon E Fisher; David J Amor; Ingrid E Scheffer; Melanie Bahlo Journal: Mol Psychiatry Date: 2022-09-18 Impact factor: 13.437
Authors: Angela Morgan; Ruth Braden; Maggie M K Wong; Estelle Colin; David Amor; Frederique Liégeois; Siddharth Srivastava; Adam Vogel; Varoona Bizaoui; Kara Ranguin; Simon E Fisher; Bregje W van Bon Journal: Eur J Hum Genet Date: 2021-04-27 Impact factor: 5.351
Authors: Anna Maria Chilosi; Irina Podda; Ivana Ricca; Alessandro Comparini; Beatrice Franchi; Simona Fiori; Rosa Pasquariello; Claudia Casalini; Paola Cipriani; Filippo Maria Santorelli Journal: J Pers Med Date: 2022-02-19
Authors: Beate Peter; Jennifer Davis; Sarah Cotter; Alicia Belter; Emma Williams; Melissa Stumpf; Laurel Bruce; Linda Eng; Yookyung Kim; Lizbeth Finestack; Carol Stoel-Gammon; Delaney Williams; Nancy Scherer; Mark VanDam; Nancy Potter Journal: Am J Speech Lang Pathol Date: 2021-10-19 Impact factor: 4.018
Authors: Amaia Carrion-Castillo; Sara B Estruch; Ben Maassen; Barbara Franke; Clyde Francks; Simon E Fisher Journal: Hum Genet Date: 2021-06-02 Impact factor: 4.132
Authors: Dóra Nagy; Sarah Verheyen; Kristen M Wigby; Artem Borovikov; Artem Sharkov; Valerie Slegesky; Austin Larson; Christina Fagerberg; Charlotte Brasch-Andersen; Maria Kibæk; Ingrid Bader; Rebecca Hernan; Frances A High; Wendy K Chung; Jolanda H Schieving; Jana Behunova; Mateja Smogavec; Franco Laccone; Martina Witsch-Baumgartner; Joachim Zobel; Hans-Christoph Duba; Denisa Weis Journal: Genes (Basel) Date: 2022-01-15 Impact factor: 4.141