LOCALIZATION OF A GENE IMPLICATED IN A SEVERE SPEECH AND LANGUAGE DISORDER

Between 2 and 5% of children who are otherwise unimpaired have signifi cant difficulties in acquiring expressive and/or receptive language, d espite adequate intelligence and opportunity(1,2) While twin studies i ndicate a significant role for genetic factors in developmental disord ers of speech and language(1), the majority of families segregating su ch disorders show complex patterns of inheritance, and are thus not am enable for conventional linkage analysis(2). A rare exception is the K E family, a large three-generation pedigree in which approximately hal f of the members are affected with a severe speech and language disord er which appears to be transmitted as an autosomal dominant monogenic trait(3). This family has been widely publicised as suffering primaril y from a defect in the use of grammatical suffixation rules(4-7), 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 affected(8-10). in addition, affected memb ers have a severe orofacial dyspraxia, and their speech is largely inc omprehensible to the naive listener(10). We initiated a genome-wide se arch for linkage in the KE family and have identified a region on chro mosome 7 which co-segregates with the speech and language disorder (ma ximum lod score = 6.62 at theta = 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 (d esignated SPCH1) to a 5.6-cM interval in 7q31, thus providing an impor tant step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental proces s that culminates in speech and language.