Localisation of a gene implicated in a severe speech and language disorder

Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity^1,2. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language¹, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis². A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait³. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixa-tion rules⁴⁻⁷, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected⁸⁻¹⁰. In addition, affected members have a severe orofa-cial dyspraxia, and their speech is largely incomprehensible to the naive listener¹⁰. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.

1. Bishop, D.V.M., North, T. & Donlan, C. Genetic basis of specific language impairment: evidence from a twin study. Dev. Med. Child Neurol. 37, 56−71 (1995). | PubMed  | ISI | ChemPort |
2. Smith, S.D., Gilger, J.W. & Pennington, B.F. Dyslexia and other specific learning disorders, in Principles and Practice of Medical Genetics (eds. D.L. Rimoin, J.M. Connor & R.E. Pyeritz) 1767−1789 (Churchill Livingston, New York, 1996).
3. Hurst, J.A., Baraitser, M., Auger, E., Graham, F. & Norell, S. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 32, 347−355 (1990).
4. Gopnik, M. Feature-blind grammar and dysphasia. Nature 344, 715 (1990). | Article | PubMed  | ISI | ChemPort |
5. Gopnik, M. & Crago, M.B. Familial aggregation of a developmental language disorder. Cognition 39, 1−50 (1991). | Article | PubMed  | ISI | ChemPort |
6. Pinker, S. Rules of language. Science 253, 530−535 (1991). | PubMed  | ISI | ChemPort |
7. Pinker, S. The Language Instinct. (Alien Lane, London, 1994).
8. Fletcher, P. Speech and language defects. Nature 346, 226 (1990). | Article |
9. Vargha-Khadem, F. & Passingham, R.E. Speech and laguage defects. Nature 346, 226 (1990). | Article | PubMed  |
10. 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. Natal. Acad. Sci. USA 92, 930−933 (1995). | ChemPort |
11. Maynard Smith, J. & Szathmary, E. The Major Transitions in Evolution. (W.H. Freeman, Oxford, 1995).
12. Reed, P.W. et al. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nature Genet. 7, 390−395 (1994). | PubMed  | ISI | ChemPort |
13. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152−154 (1996). | Article | PubMed  | ISI | ChemPort |
14. Schuler, G.D. et al. A gene map of the human genome. Science 274, 540−546 (1996). | Article | PubMed  | ISI | ChemPort |
15. Bouffard, G.G. et al. A physical map of human chromosome 7: an integrated YAC contig map with average STS spacing of 79 kb. Genome Res. 7, 673−692 (1997). | PubMed  | ISI | ChemPort |
16. Schinzel, A. Human Genetics Database. (Oxford University Press, Oxford, 1997).
17. Sarda, P., Turleau, C., Cabanis, M.-O., Jalaguier, J., de Grouchy, J. & Bonnet, H. Interstitial deletion in the long arm of chromosome 7. Ann. Genet. 31, 258−261 (1988). | PubMed  | ISI | ChemPort |
18. The international Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum. Mol. Genet (in press).
19. Lathrop, G.M., Lalouel, J.-M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natal. Acad. Sci. USA 81, 3443−3446 (1984). | ChemPort |
20. O'Connell, J.R. & Weeks, D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recording and fuzzy inheritance. Nature Genet. 11, 402−408 (1995). | PubMed  | ChemPort |
21. Sobel, E. & Lange, K. Descent graphs in pedigree analysis: applications to haplotyping, location scores and marker sharing statistics. Am. J. Hum. Genet. 58, 1323−1337 (1996). | ISI |

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