Vol. 59, No. 3, 2007
Issue release date: June 2007
Folia Phoniatr Logop 2007;59:130–140
Main Report
Add to my selection

Molecular Windows into Speech and Language Disorders

Fisher S.E.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
email Corresponding Author

 goto top of outline Key Words

  • Human genome
  • Gene mapping
  • Developmental language disorders
  • Verbal dyspraxia
  • FOXP2 gene
  • Cultured neurons

 goto top of outline Abstract

Why do some children fail to acquire speech and language skills despite adequate environmental input and overtly normal neurological and anatomical development? It has been suspected for several decades, based on indirect evidence, that the human genome might hold some answers to this enigma. These suspicions have recently received dramatic confirmation with the discovery of specific genetic changes which appear sufficient to derail speech and language development. Indeed, researchers are already using information from genetic studies to aid early diagnosis and to shed light on the neural pathways that are perturbed in these inherited forms of speech and language disorder. Thus, we have entered an exciting era for dissecting the neural bases of human communication, one which takes genes and molecules as a starting point. In the current article I explain how this recent paradigm shift has occurred and describe the new vistas that have opened up. I demonstrate ways of bridging the gaps between molecules, neurons and the brain, which will provide a new understanding of the aetiology of speech and language impairments.

Copyright © 2007 S. Karger AG, Basel

 goto top of outline References
  1. Stephenson S: Six cases of congenital word-blindness affecting three generations of one family. Ophthalmoscope 1907;5:482–484.
  2. Thomas CJ: Congenital ‘word-blindness’ and its treatment. Ophthalmoscope 1905;3:380–385.
  3. Shaywitz SE, Shaywitz BA: Dyslexia (specific reading disability). Biol Psychiatry 2005;57:1301–1309.
  4. Neils J, Aram DM: Family history of children with developmental language disorders. Percept Mot Skills 1986;63:655–658.
  5. Lewis BA, Ekelman BL, Aram DM: A familial study of severe phonological disorders. J Speech Hear Res 1989;32:713–724.
  6. Tallal P, Ross R, Curtiss S: Familial aggregation in specific language impairment. J Speech Hear Disord 1989;54:167–173.
  7. Tomblin JB: Familial concentration of developmental language impairment. J Speech Hear Disord 1989;54:287–295.
  8. Lahey M, Edwards J: Specific language impairment: preliminary investigation of factors associated with family history and with patterns of language performance. J Speech Hear Res 1995;38:643–657.
  9. Lewis BA, Thompson LA: A study of developmental speech and language disorders in twins. J Speech Hear Res 1992;35:1086–1094.
  10. Bishop DV, North T, Donlan C: Genetic basis of specific language impairment: evidence from a twin study. Dev Med Child Neurol 1995;37:56–71.
  11. Tomblin JB, Buckwalter PR: Heritability of poor language achievement among twins. J Speech Lang Hear Res 1998;41:188–199.
  12. Dale PS, Simonoff E, Bishop DV, Eley TC, Oliver B, Price TS, Purcell S, Stevenson J, Plomin R: Genetic influence on language delay in two-year-old children. Nat Neurosci 1998;1:324–328.
  13. Bishop DV, Bishop SJ, Bright P, James C, Delaney T, Tallal P: Different origin of auditory and phonological processing problems in children with language impairment: evidence from a twin study. J Speech Lang Hear Res 1999;42:155–168.
  14. Viding E, Spinath FM, Price TS, Bishop DV, Dale PS, Plomin R: Genetic and environmental influence on language impairment in 4-year-old same-sex and opposite-sex twins. J Child Psychol Psychiatry 2004;45:315–325.
  15. Fisher SE: Tangled webs: tracing the connections between genes and cognition. Cognition 2006;101:270–297.
  16. Botstein D, Risch N: Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003;33(suppl):228–237.
  17. Bell JI: The double helix in clinical practice. Nature 2003;421:414–416.
  18. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, Sharon E, Spector Y, Bentwich Z: Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 2005;37:766–770.
  19. Berezikov E, Thuemmler F, van Laake LW, Kondova I, Bontrop R, Cuppen E, Plasterk RH: Diversity of microRNAs in human and chimpanzee brain. Nat Genet 2006;38:1375–1377.
  20. Willingham AT, Gingeras TR: TUF love for ‘junk’ DNA. Cell 2006;125:1215–1220.
  21. Wolfsberg TG, McEntyre J, Schuler GD: Guide to the draft human genome. Nature 2001;409:824–826.
  22. International Hapmap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
  23. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME: Global variation in copy number in the human genome. Nature 2006;444:444–454.
  24. Reich DE, Lander ES: On the allelic spectrum of human disease. Trends Genet 2001;17:502–510.
  25. Antonarakis SE, Beckmann JS: Mendelian disorders deserve more attention. Nat Rev Genet 2006;7:277–282.
  26. Fisher SE, Lai CS, Monaco AP: Deciphering the genetic basis of speech and language disorders. Annu Rev Neurosci 2003;26:57–80.
  27. Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 2002;71:45–55.
  28. Bartlett CW, Flax JF, Logue MW, Smith BJ, Vieland VJ, Tallal P, Brzustowicz LM: Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment. Hum Hered 2004;57:10–20.
  29. The SLI Consortium: A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 2002;70:384–398.
  30. The SLI Consortium: Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet 2004;74:1225–1238.
  31. Newbury DF, Bishop DV, Monaco AP: Genetic influences on language impairment and phonological short-term memory. Trends Cogn Sci 2005;9:528–534.
  32. Bishop DV, North T, Donlan C: Nonword repetition as a behavioural marker for inherited language impairment: evidence from a twin study. J Child Psychol Psychiatry 1996;37:391–403.
  33. Gathercole SE, Willis CS, Baddeley AD, Emslie H: The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory 1994;2:103–127.
  34. Gathercole SE, Baddeley AD: Phonological memory deficits in language disordered children – is there a causal connection? J Memory Lang 1990;29:336–360.
  35. Bishop DV: Genetic influences on language impairment and literacy problems in children: same or different? J Child Psychol Psychiatry 2001;42:189–198.
  36. Lewis BA, Shriberg LD, Freebairn LA, Hansen AJ, Stein CM, Taylor HG, Iyengar SK: The genetic bases of speech sound disorders: evidence from spoken and written language. J Speech Lang Hear Res 2006;49:1294–1312.
  37. Smith SD, Pennington BF, Boada R, Shriberg LD: Linkage of speech sound disorder to reading disability loci. J Child Psychol Psychiatry 2005;46:1057–1066.
  38. Stein CM, Schick JH, Gerry Taylor H, Shriberg LD, Millard C, Kundtz-Kluge A, Russo K, Minich N, Hansen A, Freebairn LA, Elston RC, Lewis BA, Iyengar SK: Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading. Am J Hum Genet 2004;74:283–297.
  39. Fisher SE, DeFries JC: Developmental dyslexia: genetic dissection of a complex cognitive trait. Nat Rev Neurosci 2002;3:767–780.
  40. Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC: Quantitative trait locus for reading disability on chromosome 6. Science 1994;266:276–279.
  41. Smith SD, Kimberling WJ, Pennington BF, Lubs HA: Specific reading disability: identification of an inherited form through linkage analysis. Science 1983;219:1345–1347.
  42. Cope N, Harold D, Hill G, Moskvina V, Stevenson J, Holmans P, Owen MJ, O’Donovan MC, Williams J: Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. Am J Hum Genet 2005;76:581–591.
  43. Francks C, Paracchini S, Smith SD, Richardson AJ, Scerri TS, Cardon LR, Marlow AJ, MacPhie IL, Walter J, Pennington BF, Fisher SE, Olson RK, DeFries JC, Stein JF, Monaco AP: A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. Am J Hum Genet 2004;75:1046–1058.
  44. Meng H, Smith SD, Hager K, Held M, Liu J, Olson RK, Pennington BF, DeFries JC, Gelernter J, O’Reilly-Pol T, Somlo S, Skudlarski P, Shaywitz SE, Shaywitz BA, Marchione K, Wang Y, Paramasivam M, LoTurco JJ, Page GP, Gruen JR: DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005;102:17053–17058.
  45. Schumacher J, Anthoni H, Dahdouh F, Konig IR, Hillmer AM, Kluck N, Manthey M, Plume E, Warnke A, Remschmidt H, Hulsmann J, Cichon S, Lindgren CM, Propping P, Zucchelli M, Ziegler A, Peyrard-Janvid M, Schulte-Korne G, Nothen MM, Kere J: Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am J Hum Genet 2006;78:52–62.
  46. Paracchini S, Thomas A, Castro S, Lai C, Paramasivam M, Wang Y, Keating BJ, Taylor JM, Hacking DF, Scerri T, Francks C, Richardson AJ, Wade-Martins R, Stein JF, Knight JC, Copp AJ, LoTurco JJ, Monaco AP: The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum Mol Genet 2006;15:1659–1666.
  47. Fisher SE, Francks C: Genes, cognition and dyslexia: learning to read the genome. Trends Cogn Sci 2006;10:250–257.
  48. McGrath LM, Smith SD, Pennington BF: Breakthroughs in the search for dyslexia candidate genes. Trends Mol Med 2006;12:333–341.
  49. Hurst JA, Baraitser M, Auger E, Graham F, Norell S: An extended family with a dominantly inherited speech disorder. Dev Med Child Neurol 1990;32:352–355.
  50. Gopnik M: Feature-blind grammar and dysphasia. Nature 1990;344:715.
  51. Gopnik M, Crago MB: Familial aggregation of a developmental language disorder. Cognition 1991;39:1–50.
  52. Watkins KE, Dronkers NF, Vargha-Khadem F: Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain 2002;125:452–464.
  53. Vargha-Khadem F, Watkins K, Alcock K, Fletcher P, Passingham R: Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc Natl Acad Sci USA 1995;92:930–933.
  54. Pinker S: The Language Instinct. London, Allen Lane, 1994.
  55. Marcus GF, Fisher SE: FOXP2 in focus: what can genes tell us about speech and language? Trends Cogn Sci 2003;7:257–262.
  56. Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME: Localisation of a gene implicated in a severe speech and language disorder. Nat Genet 1998;18:168–170.
  57. Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison DC, Green ED, Vargha-Khadem F, Monaco AP: The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am J Hum Genet 2000;67:357–368.
  58. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP: A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001;413:519–523.
  59. Vernes SC, Nicod J, Elahi FM, Coventry JA, Kenny N, Coupe AM, Bird LE, Davies KE, Fisher SE: Functional genetic analysis of mutations implicated in a human speech and language disorder. Hum Mol Genet 2006;15:3154–3167.
  60. Fisher SE: Dissection of molecular mechanisms underlying speech and language disorders. Appl Psycholing 2005;26:111–128.

    External Resources

  61. Belton E, Salmond CH, Watkins KE, Vargha-Khadem F, Gadian DG: Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Hum Brain Mapp 2003;18:194–200.
  62. Watkins KE, Vargha-Khadem F, Ashburner J, Passingham RE, Connelly A, Friston KJ, Frackowiak RS, Mishkin M, Gadian DG: MRI analysis of an inherited speech and language disorder: structural brain abnormalities. Brain 2002;125:465–478.
  63. Liegeois F, Baldeweg T, Connelly A, Gadian DG, Mishkin M, Vargha-Khadem F: Language fMRI abnormalities associated with FOXP2 gene mutation. Nat Neurosci 2003;6:1230–1237.
  64. Carlsson P, Mahlapuu M: Forkhead transcription factors: key players in development and metabolism. Dev Biol 2002;250:1–23.
  65. Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS: Fox’s in development and disease. Trends Genet 2003;19:339–344.
  66. Stroud JC, Wu Y, Bates DL, Han A, Nowick K, Paabo S, Tong H, Chen L: Structure of the forkhead domain of FOXP2 bound to DNA. Structure 2006;14:159–166.
  67. Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA: Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. Am J Med Genet A 2003;118:172–175.

    External Resources

  68. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP: FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002;70:1318–1327.
  69. Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC: Evaluation of FOXP2 as an autism susceptibility gene. Am J Med Genet 2002;114:566–569.
  70. MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE: Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 2005;76:1074–1080.
  71. Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA: Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res 2006;49:500–525.
  72. Zeesman S, Nowaczyk MJ, Teshima I, Roberts W, Cardy JO, Brian J, Senman L, Feuk L, Osborne LR, Scherer SW: Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A 2006;140:509–514.
  73. Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B, Hartung D, Innes M, Kerem B, Nowaczyk MJ, Rivlin J, Roberts W, Senman L, Summers A, Szatmari P, Wong V, Vincent JB, Zeesman S, Osborne LR, Cardy JO, Kere J, Scherer SW, Hannula-Jouppi K: Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet 2006;79:965–972.
  74. Kim TH, Ren B: Genome-wide analysis of protein-DNA interactions. Annu Rev Genomics Hum Genet 2006;7:81–102.
  75. Lai CS, Gerrelli D, Monaco AP, Fisher SE, Copp AJ: FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 2003;126:2455–2462.
  76. Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA: Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J Neurosci 2004;24:3152–3163.
  77. Ferland RJ, Cherry TJ, Preware PO, Morrisey EE, Walsh CA: Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. J Comp Neurol 2003;460:266–279.
  78. Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C: FoxP2 expression in avian vocal learners and non-learners. J Neurosci 2004;24:3164–3175.
  79. Bonkowsky JL, Chien CB: Molecular cloning and developmental expression of foxP2 in zebrafish. Dev Dyn 2005;234:740-746.
  80. Fisher SE, Marcus GF: The eloquent ape: genes, brains and the evolution of language. Nat Rev Genet 2006;7:9–20.
  81. Shu W, Yang H, Zhang L, Lu MM, Morrisey EE: Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem 2001;276:27488–27497.
  82. White SA, Fisher SE, Geschwind DH, Scharff C, Holy TE: Singing mice, songbirds, and more: models for FOXP2 function and dysfunction in human speech and language. J Neurosci 2006;26:10376–10379.
  83. Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD: Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci USA 2005;102:9643–9648.
  84. Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Paabo S: Molecular evolution of FOXP2, a gene involved in speech and language. Nature 2002;418:869–872.
  85. Zhang J, Webb DM, Podlaha O: Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics 2002;162:1825–1835.
  86. Somerville MJ, Mervis CB, Young EJ, Seo EJ, del Campo M, Bamforth S, Peregrine E, Loo W, Lilley M, Perez-Jurado LA, Morris CA, Scherer SW, Osborne LR: Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 2005;353:1694–1701.
  87. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007;39:25–27.
  88. Fisher SE: On genes, speech, and language. N Engl J Med 2005;353:1655–1657.

 goto top of outline Author Contacts

Dr. Simon E. Fisher
Head of Molecular Neuroscience
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
Oxford OX3 7BN (UK)
Tel. +44 1865 287 647, Fax +44 1865 287 533, E-Mail simon.fisher@well.ox.ac.uk

 goto top of outline Article Information

Number of Print Pages : 11
Number of Figures : 0, Number of Tables : 0, Number of References : 88

 goto top of outline Publication Details

Folia Phoniatrica et Logopaedica (International Journal of Phoniatrics, Speech Therapy and Communication Pathology)

Vol. 59, No. 3, Year 2007 (Cover Date: June 2007)

Journal Editor: Schutte, H.K. (Groningen)
ISSN: 1021–7762 (print), 1421–9972 (Online)

For additional information: http://www.karger.com/FPL

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.