Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 Sep;41(9):652–657. doi: 10.1136/jmg.2003.012294

Genomewide scan identifies susceptibility locus for dyslexia on Xq27 in an extended Dutch family

C G F de Kovel 1, F Hol 1, J Heister 1, J Willemen 1, L Sandkuijl 1, B Franke 1, G Padberg 1
PMCID: PMC1735895  PMID: 15342694

Abstract

Context: Dyslexia is a common disorder with a strong genetic component, but despite significant research effort, the aetiology is still largely unknown.

Objective: To identify loci contributing to dyslexia risk.

Methods: This was a genomewide linkage analysis in a single large family. Dutch families with at least two first degree relatives suffering from dyslexia participated in the study. Participants were recruited through an advertisement campaign in papers and magazines. The main outcome measure was linkage between genetic markers and dyslexia phenotype.

Results: Using parametric linkage analysis, we found strong evidence for a locus influencing dyslexia on Xq27.3 (multipoint lod = 3.68). Recombinations in two family members flanked an 8 cM region, comprising 11 currently confirmed genes. All four males carrying the risk haplotype had very low scores on the reading tests. The presentation in females was more variable, but 8/9 females carrying the risk haplotype were diagnosed dyslexic by our composite score, so we considered the putative risk allele to be dominant with reduced penetrance. Linkage was not found in an additional collection of affected sibling pairs.

Conclusions: A locus influencing dyslexia risk is probably located between markers DXS1227 and DXS8091 on the X chromosome, closely situated to a locus indicated by a published genome scan of English sibling pairs. Although the locus may not be a common cause for dyslexia, the relatively small and gene poor region offers hope to identify the responsible gene.

Full Text

The Full Text of this article is available as a PDF (185.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bardoni Barbara, Mandel Jean-Louis. Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr Opin Genet Dev. 2002 Jun;12(3):284–293. doi: 10.1016/s0959-437x(02)00300-3. [DOI] [PubMed] [Google Scholar]
  2. Cardon L. R., Smith S. D., Fulker D. W., Kimberling W. J., Pennington B. F., DeFries J. C. Quantitative trait locus for reading disability on chromosome 6. Science. 1994 Oct 14;266(5183):276–279. doi: 10.1126/science.7939663. [DOI] [PubMed] [Google Scholar]
  3. Chomez P., De Backer O., Bertrand M., De Plaen E., Boon T., Lucas S. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001 Jul 15;61(14):5544–5551. [PubMed] [Google Scholar]
  4. Fagerheim T., Raeymaekers P., Tønnessen F. E., Pedersen M., Tranebjaerg L., Lubs H. A. A new gene (DYX3) for dyslexia is located on chromosome 2. J Med Genet. 1999 Sep;36(9):664–669. [PMC free article] [PubMed] [Google Scholar]
  5. Fisher Simon E., DeFries John C. Developmental dyslexia: genetic dissection of a complex cognitive trait. Nat Rev Neurosci. 2002 Oct;3(10):767–780. doi: 10.1038/nrn936. [DOI] [PubMed] [Google Scholar]
  6. Fisher Simon E., Francks Clyde, Marlow Angela J., MacPhie I. Laurence, Newbury Dianne F., Cardon Lon R., Ishikawa-Brush Yumiko, Richardson Alex J., Talcott Joel B., Gayán Javier. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet. 2001 Dec 17;30(1):86–91. doi: 10.1038/ng792. [DOI] [PubMed] [Google Scholar]
  7. Grigorenko E. L., Wood F. B., Meyer M. S., Hart L. A., Speed W. C., Shuster A., Pauls D. L. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am J Hum Genet. 1997 Jan;60(1):27–39. [PMC free article] [PubMed] [Google Scholar]
  8. Grigorenko E. L., Wood F. B., Meyer M. S., Pauls D. L. Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation. Am J Hum Genet. 2000 Feb;66(2):715–723. doi: 10.1086/302755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. James W. H. The sex ratios of dyslexic children and their sibs. Dev Med Child Neurol. 1992 Jun;34(6):530–533. doi: 10.1111/j.1469-8749.1992.tb11474.x. [DOI] [PubMed] [Google Scholar]
  10. Kaminen N., Hannula-Jouppi K., Kestilä M., Lahermo P., Muller K., Kaaranen M., Myllyluoma B., Voutilainen A., Lyytinen H., Nopola-Hemmi J. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32. J Med Genet. 2003 May;40(5):340–345. doi: 10.1136/jmg.40.5.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kong A., Cox N. J. Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet. 1997 Nov;61(5):1179–1188. doi: 10.1086/301592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  13. Lathrop G. M., Lalouel J. M., White R. L. Construction of human linkage maps: likelihood calculations for multilocus linkage analysis. Genet Epidemiol. 1986;3(1):39–52. doi: 10.1002/gepi.1370030105. [DOI] [PubMed] [Google Scholar]
  14. Marín Oscar, Plump Andrew S., Flames Nuria, Sánchez-Camacho Cristina, Tessier-Lavigne Marc, Rubenstein John L. R. Directional guidance of interneuron migration to the cerebral cortex relies on subcortical Slit1/2-independent repulsion and cortical attraction. Development. 2003 May;130(9):1889–1901. doi: 10.1242/dev.00417. [DOI] [PubMed] [Google Scholar]
  15. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Morris D. W., Robinson L., Turic D., Duke M., Webb V., Milham C., Hopkin E., Pound K., Fernando S., Easton M. Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q. Hum Mol Genet. 2000 Mar 22;9(5):843–848. doi: 10.1093/hmg/9.5.843. [DOI] [PubMed] [Google Scholar]
  17. Nopola-Hemmi J., Myllyluoma B., Haltia T., Taipale M., Ollikainen V., Ahonen T., Voutilainen A., Kere J., Widén E. A dominant gene for developmental dyslexia on chromosome 3. J Med Genet. 2001 Oct;38(10):658–664. doi: 10.1136/jmg.38.10.658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. O'Connell J. R., Weeks D. E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998 Jul;63(1):259–266. doi: 10.1086/301904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pennington B. F., Gilger J. W., Pauls D., Smith S. A., Smith S. D., DeFries J. C. Evidence for major gene transmission of developmental dyslexia. JAMA. 1991 Sep 18;266(11):1527–1534. [PubMed] [Google Scholar]
  20. Petryshen T. L., Kaplan B. J., Hughes M. L., Tzenova J., Field L. L. Supportive evidence for the DYX3 dyslexia susceptibility gene in Canadian families. J Med Genet. 2002 Feb;39(2):125–126. doi: 10.1136/jmg.39.2.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rabin M., Wen X. L., Hepburn M., Lubs H. A., Feldman E., Duara R. Suggestive linkage of developmental dyslexia to chromosome 1p34-p36. Lancet. 1993 Jul 17;342(8864):178–178. doi: 10.1016/0140-6736(93)91384-x. [DOI] [PubMed] [Google Scholar]
  22. Redolfi E., Montagna C., Mumm S., Affer M., Susani L., Reinbold R., Hol F., Vezzoni P., Cimino M., Zucchi I. Identification of CXorf1, a novel intronless gene in Xq27.3, expressed in human hippocampus. DNA Cell Biol. 1998 Dec;17(12):1009–1016. doi: 10.1089/dna.1998.17.1009. [DOI] [PubMed] [Google Scholar]
  23. Redolfi E., Pizzuti A., Di Bacco A., Susani L., Labella T., Affer M., Montagna C., Reinbold R., Mumm S., Vezzoni P. Mapping of the MYCL2 processed gene to Xq22-23 and identification of an additional L MYC-related sequence in Xq27.2. FEBS Lett. 1999 Mar 12;446(2-3):273–277. doi: 10.1016/s0014-5793(99)00243-4. [DOI] [PubMed] [Google Scholar]
  24. Schulte-Körne G. Annotation: Genetics of reading and spelling disorder. J Child Psychol Psychiatry. 2001 Nov;42(8):985–997. doi: 10.1111/1469-7610.00797. [DOI] [PubMed] [Google Scholar]
  25. Schulte-Körne G., Grimm T., Nöthen M. M., Müller-Myhsok B., Cichon S., Vogt I. R., Propping P., Remschmidt H. Evidence for linkage of spelling disability to chromosome 15. Am J Hum Genet. 1998 Jul;63(1):279–282. doi: 10.1086/301919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Taipale Mikko, Kaminen Nina, Nopola-Hemmi Jaana, Haltia Tuomas, Myllyluoma Birgitta, Lyytinen Heikki, Muller Kurt, Kaaranen Minna, Lindsberg Perttu J., Hannula-Jouppi Katariina. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci U S A. 2003 Sep 3;100(20):11553–11558. doi: 10.1073/pnas.1833911100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wijsman E. M., Peterson D., Leutenegger A. L., Thomson J. B., Goddard K. A., Hsu L., Berninger V. W., Raskind W. H. Segregation analysis of phenotypic components of learning disabilities. I. Nonword memory and digit span. Am J Hum Genet. 2000 Jul 31;67(3):631–646. doi: 10.1086/303044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wilson A. M., Lesaux N. K. Persistence of phonological processing deficits in college students with dyslexia who have age-appropriate reading skills. J Learn Disabil. 2001 Sep-Oct;34(5):394–400. doi: 10.1177/002221940103400501. [DOI] [PubMed] [Google Scholar]
  29. de Vries B. B., Wiegers A. M., Smits A. P., Mohkamsing S., Duivenvoorden H. J., Fryns J. P., Curfs L. M., Halley D. J., Oostra B. A., van den Ouweland A. M. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet. 1996 May;58(5):1025–1032. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES