| Developmental dyslexia is a common disorder affecting 5-10% of the population, and it is defined as a specific deficit in reading, despite adequate overall intelligence and educational opportunity. A wide, heterogeneous constellation of deficits in core behavioral processes (termed "endophenotypes") underlie (and perhaps contribute to) the definitive impairment in reading observed in dyslexia, including deficits in phonological processing, short term and working memory, rapid auditory processing, and visual attention. Neurologically, dyslexia is characterized by subtle anomalies (i.e., not gross, visible distortions) within the brain. Neuroimaging studies have revealed region-specific changes in gray and white matter in the brains of dyslexic individuals, and post mortem studies of brains from dyslexic patients have reported that focal disruptions of neuronal migration are also associated with the disorder. The precise etiology of developmental dyslexia is unknown. Recent genetic and epidemiological work has identified several genes that confer risk of developing the disorder (candidate dyslexia susceptibility genes, or CDSGs). Efforts to elucidate clear gene-behavior relationships in dyslexia have been hampered by the characteristic phenotypic heterogeneity of the disorder. It has been suggested that genotype-phenotype relationships in dyslexia might be better defined by associating genetic variants with specific endophenotypes, rather than the broad categorical diagnosis of dyslexia. Within the studies presented here, we have used an animal model to assess neuroanatomical and behavioral outcomes following embryonic disruption of the rodent homologs of two candidate dyslexia susceptibility genes, DYX1C1 and KIAA0319. Our results demonstrate that each of these genes plays a distinct role in neuronal migration and subsequent brain development, that disruption of each gene differentially affects abilities in behavioral domains relevant to dyslexia (rapid auditory processing, working memory, attention), and that the observed phenotype varies if multiple genes are disrupted simultaneously. These results indicate significant differences in the behavioral and neuroanatomical effects of disruption of these genes, and have important implications for future research on genotype-phenotype relationships in dyslexia, including the possible use of gene-behavior relationships to define subtypes of the disorder, and ultimately to create specifically-tailored behavioral interventions and therapies for affected individuals. |
