Dyslexia and dysgraphia are common and complex disorders are common and complex disorders that have long-term educational, economic, and social repercussions. Understanding the biologic basis may lead to earlier and more specific intervention. This project will investigate genetic factors involved in specific subtypes of dyslexia and dysgraphia by evaluating kindreds well-characterized from learning disabilities (LD). There are 5 specific aims. 1. To expand a bank of DNA and cell lines from pedigrees with dyslexia and/or dysgraphia. Ascertainment of probands (500 over the next five years) will be extended to grade 9, for continued recruitment of probands with combined dyslexia and dysgraphia and for increased recruitment of probands with the dysgraphia-only phenotype. 2. To continue to determine transmission patterns of LD subtypes. The language phenotype will be broadened to include morphological processes and the familial aggregation patterns and interdependence of the findings of the previous grant cycle, comorbidity of inattention as a quantitative trait and comorbidity of calculation disability will also be investigated. The LD subphenotypes most likely to have a genetic etiology will be evaluated in segregation analyses to develop models for use in linkage analyses. 3. To detect linkage of learning disabilities subtypes. Candidate regions on chromosomes 1, 2, 6, 7, and 15, already genotyped, will be evaluated for linkage to LD phenotypes and a genome-wide scan will be performed to identify other candidate regions. 4. To perform fine scale mapping of the most promising regions identified in the linkage analyses to enable gene identification. 5. To optimize the UWLDC database and to perform quality control analyses of the data. This Project is carried out in close collaboration with the Clinical Core for the careful phenotyping and with the Statistical Core for all statistical genetic analyses. The goals will be expedited by applying emerging powerful analysis methods. Project III is also linked to Projects I and II in extending the language phenotype to include morphologic processes. Project III is linked to Project IV via an exploratory study of the feasibility of using fMRS measurements as the quantitative trait.
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