Molecular Genetics of Dyslexia

Abstract

Dyslexia is a specific impairment in learning to read which affects 5–10% of school‐age children. Family and twin studies have shown that dyslexia is caused in large part by genetic factors. Dyslexia is most likely the result of the interplay of multiple genetic and environmental factors. Recently, several genes have been proposed as candidates for dyslexia susceptibility, including DYX1C1 on chromosome 15, KIAA0319 and DCDC2 on chromosome 6, ROBO1 on chromosome 3 and MRPL19 and C2ORF3 on chromosome 2. Interestingly, these genes share a putative role in brain development. No functional genetic variant has been identified for any of the genes but the study of their function offers for the first time new insights in the understanding of the biology of dyslexia and the mechanisms underlying cognition and brain function.

Key concepts

  • Several genes have recently been proposed as candidates for dyslexia susceptibility.

  • Most of these genes have shown association in independent samples of individuals with dyslexia.

  • A specific risk haplotype has been identified for the KIAA0319 gene.

  • Most of the candidates have been implicated in brain development.

  • No functional mutations have been identified for any of the genes.

  • Gene expression has been proposed as the main mechanism linking genetic susceptibility to the development of dyslexia

Keywords: reading; complex trait; association study; cognitive functions; neuronal migration

Figure 1.

Genomic location of dyslexia candidate genes. The location of the dyslexia candidates is shown in the context of the dyslexia susceptibility (DYX) loci identified through linkage studies and represented in the figure by red solid bars. The black arrows indicate the direction of transcription of the genes.

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References

Anthoni H, Zucchelli M, Matsson H et al. (2007) A locus on 2p12 containing the co‐regulated MRPL19 and C2ORF3 genes is associated to dyslexia. Human Molecular Genetics 16: 667–677.

Bellini G, Bravaccio C, Calamoneri F et al. (2005) No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy. Journal of Molecular Neuroscience 27: 311–314.

Brkanac Z, Chapman NH, Matsushita MM et al. (2007) Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B: 556–560.

Bycroft M, Bateman A, Clarke J et al. (1999) The structure of a PKD domain from polycystin‐1: implications for polycystic kidney disease. EMBO Journal 18: 297–305.

Chapman NH, Igo RP, Thomson JB et al. (2004) Linkage analyses of four regions previously implicated in dyslexia: confirmation of a locus on chromosome 15q. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 131: 67–75.

Cope N, Harold D, Hill G et al. (2005a) Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. American Journal of Human Genetics 76: 581–591.

Cope NA, Hill G, van den Bree M et al. (2005b) No support for association between dyslexia susceptibility 1 candidate 1 and developmental dyslexia. Molecular Psychiatry 10: 237–238.

DeFries JC and Fulker DW (1985) Multiple regression analysis of twin data. Behavior Genetics 15: 467–473.

DeFries JC, Fulker DW and LaBuda MC (1987) Evidence for a genetic aetiology in reading disability of twins. Nature 329: 537–539.

Fagerheim T, Raeymaekers P, Tonnessen FE et al. (1999) A new gene (DYX3) for dyslexia is located on chromosome 2. Journal of Medical Genetics 36: 664–669.

Fisher SE and DeFries JC (2002) Developmental dyslexia: genetic dissection of a complex cognitive trait. Nature Reviews. Neuroscience 3: 767–780.

Fisher SE and Francks C (2006) Genes, cognition and dyslexia: learning to read the genome. Trends in Cognitive Sciences 10: 250–257.

Fisher SE, Francks C, Marlow AJ et al. (2002) Independent genome‐wide scans identify a chromosome 18 quantitative‐trait locus influencing dyslexia. Nature Genetics 30: 86–91.

Fisher SE, Marlow AJ, Lamb J et al. (1999) A quantitative‐trait locus on chromosome 6p influences different aspects of developmental dyslexia. American Journal of Human Genetics 64: 146–156.

Francks C, Paracchini S, Smith SD et al. (2004) A 77‐kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. American Journal of Human Genetics 75: 1046–1058.

Galaburda AM and Kemper TL (1979) Cytoarchitectonic abnormalities in developmental dyslexia: a case study. Annals of Neurology 6: 94–100.

Galaburda AM, LoTurco J, Ramus F, Fitch RH and Rosen GD (2006) From genes to behavior in developmental dyslexia. Nature Neuroscience 9: 1213–1217.

Galaburda AM, Sherman GF, Rosen GD, Aboitiz F and Geschwind N (1985) Developmental dyslexia: four consecutive patients with cortical anomalies. Annals of Neurology 18: 222–233.

Grigorenko EL, Wood FB, Meyer MS et al. (1997) Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. American Journal of Human Genetics 60: 27–39.

Habib M (2000) The neurological basis of developmental dyslexia: an overview and working hypothesis. Brain 123(part 12): 2373–2399.

Hannula‐Jouppi K, Kaminen‐Ahola N, Taipale M et al. (2005) The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genetics 1: e50.

Harold D, Paracchini S, Scerri T et al. (2006) Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Molecular Psychiatry 11: 1085–1091, 1061.

Kidd T, Brose K, Mitchell KJ et al. (1998) Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92: 205–215.

Lindgren SD, De Renzi E and Richman LC (1985) Cross‐national comparisons of developmental dyslexia in Italy and the United States. Child Development 56: 1404–1417.

Lovegrove WJ, Bowling A, Badcock D and Blackwood M (1980) Specific reading disability: differences in contrast sensitivity as a function of spatial frequency. Science 210: 439–440.

Marino C, Giorda R, Luisa Lorusso M et al. (2005) A family based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia. European Journal of Human Genetics 13: 491–499.

McGrath LM, Smith SD and Pennington BF (2006) Breakthroughs in the search for dyslexia candidate genes. Trends in Molecular Medicine 12: 333–341.

Meda SA, Gelernter J, Gruen JR et al. (2008) Polymorphism of DCDC2 reveals differences in cortical morphology of healthy individuals—a preliminary voxel based morphometry study. Journal Brain Imaging and Behavior 2: 21–26.

Meng H, Hager K, Held M et al. (2005a) TDT‐association analysis of EKN1 and dyslexia in a Colorado twin cohort. Human Genetics 118: 87–90.

Meng H, Smith SD, Hager K et al. (2005b) DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proceedings of the National Academy of Sciences of the USA 102: 17053–17058.

Nicolson R, Fawcett AJ and Dean P (2001) Dyslexia, development and the cerebellum. Trends in Neurosciences 24: 515–516.

Paracchini S, Scerri T and Monaco AP (2007) The Genetic Lexicon of Dyslexia. Annual Review of Genomics and Human Genetics 8: 57–79.

Paracchini S, Steer CD, Buckingham L‐L et al. (2008) The KIAA0319 dyslexia susceptibility gene is associated with reading skills in the general population. The American Journal of Psychiatry 165: 1576–1584.

Paracchini S, Thomas A, Castro S et al. (2006) The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Human Molecular Genetics 15: 1659–1666.

Pennington BF (1990) The genetics of dyslexia. Journal of Child Psychology and Psychiatry and Allied Disciplines 31: 193–201.

Pennington BF and Gilger JW (1996) How is dyslexia transmitted? In: Chase CH, Rosen GD and Sherman GF (ed.) Developmental Dyslexia. Neural, Cognitive and Genetic Mechanisms, pp. 41–61. Baltimore, MD: York Press.

des Portes V, Francis F, Pinard JM et al. (1998) Doublecortin is the major gene causing X‐linked subcortical laminar heterotopia (SCLH). Human Molecular Genetics 7: 1063–1070.

Ramus F, Rosen S, Dakin SC et al. (2003) Theories of developmental dyslexia: insights from a multiple case study of dyslexic adults. Brain 126: 841–865.

Scerri TS, Fisher SE, Francks C et al. (2004) Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK. Journal of Medical Genetics 41: 853–857.

Schumacher J, Anthoni H, Dahdouh F et al. (2006) Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. American Journal of Human Genetics 78: 52–62.

Shaywitz SE (1998) Dyslexia. New England Journal of Medicine 338: 307–312.

SLIC (2002) A genomewide scan identifies two novel loci involved in specific language impairment. American Journal of Human Genetics 70: 384–398.

Smith SD, Kimberling WJ and Pennington BF (1991) Screening for multiple genes influencing dyslexia. Reading and Writing: An Interdisciplinary Journal 3: 285–298.

Smith SD, Kimberling WJ, Pennington BF and Lubs HA (1983) Specific reading disability: identification of an inherited form through linkage analysis. Science 219: 1345–1347.

Stein J (2001) The magnocellular theory of developmental dyslexia. Dyslexia 7: 12–36.

Taipale M, Kaminen N, Nopola‐Hemmi J et al. (2003) A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proceedings of the National Academy of Sciences of the USA 100: 11553–11558.

Tallal P (1980) Auditory temporal perception, phonics, and reading disabilities in children. Brain and Language 9: 182–198.

Tapia‐Paez I, Tammimies K, Massinen S, Roy AL and Kere J (2008) The complex of TFII‐I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia. FASEB Journal 22: 3001–3009.

Velayos‐Baeza A, Toma C, Paracchini S and Monaco AP (2008) The dyslexia‐associated gene KIAA0319 encodes highly N‐ and O‐glycosylated plasma membrane and secreted isoforms. Human Molecular Genetics 17: 859–871.

Wang Y, Paramasivam M, Thomas A et al. (2006) DYX1C1 functions in neuronal migration in developing neocortex. Neuroscience 143: 515–522.

Wigg KG, Couto JM, Feng Y et al. (2004) Support for EKN1 as the susceptibility locus for dyslexia on 15q21. Molecular Psychiatry 9: 1111–1121.

Williams J and O'Donovan MC (2006) The genetics of developmental dyslexia. European Journal of Human Genetics 14: 681–689.

Further Reading

Demonet JF, Taylor MJ and Chaix Y (2004) Developmental dyslexia. Lancet 363: 1451–1460.

Hirschhorn JN and Daly MJ (2005) Genome‐wide association studies for common diseases and complex traits. Nature Review Genetics 6: 95–108.

Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. Journal of Molecular Medicine 83: 97–109.

Nadarajah B and Parnavelas JG (2002) Modes of neuronal migration in the developing cerebral cortex. Nature Review Neuroscience 3: 423–432.

Ramus F (2004) Neurobiology of dyslexia: a reinterpretation of the data. Trends in Neurosciences 27: 720–726.

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How to Cite close
Paracchini, Silvia(Mar 2009) Molecular Genetics of Dyslexia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021474]