A genome wide screen for loci involved in specific language impairment
Approximately 4% of English-speaking children are affected by Specific Language Impairment (SLI); a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and monozygotic concordance consistently exceeds that of dizygotic twins. However, like many behavioural traits, SLI is assumed to be genetically complex with several loci contributing to the overall risk. This thesis aims to clarify the genetic mechanisms underlying Specific Language Impairment by the exploitation of recent advances in technological, genetic and statistical techniques. This goal is achieved, for the main part, through the completion of the first-ever, systematic genome-wide screen for loci involved in the disorder. A collection of 98 families was drawn from both epidemiological and clinical populations, all with probands who display severe deficits in language skills. Genome-wide linkage analyses were completed for three language-related measures and identified two regions which may harbour susceptibility gene variants for SLI, one on chromosome 16 and a second on chromosome 19. Both of these loci yielded maximum LOD scores of 3.55 and exceeded the threshold for suggestive linkage under all types of analysis performed. Fine mapping of the chromosome 19 locus with a high-density map of microsatellite markers provided further support for the role of this region in SLI but failed to narrow the area of linkage. The second section of the thesis therefore explores alternative genetic strategies that may facilitate the localisation of susceptibility variants from the genomic regions identified. Mutation screening and association analyses were performed for two candidate genes within a subset of 48 families affected by SLI. The first ⎼ numblike (NBL), or numb-related (NUMB-R) (MIM 604018) ⎼ was selected from the region of linkage on chromosome 19q and the second ⎼ Forkhead-bOX domain P2 (FOXP2) (MIM 605317) ⎼ has recently been shown to be mutated in a family with a severe speech and language disorder. Finally, I describe the mapping of a translocation breakpoint within a child affected by a severe language impairment and orofacial dyspraxia. This breakpoint lies on chromosome 2q and coincides with a putative region of linkage in both language impairment and autism. In the long-term it is hoped that techniques similar to those described here will allow the identification of the gene variants which underlie SLI allowing to the development of better diagnosis and treatment for those children with language impairments.