One of every 180 live-born infants has a chromosome abnormality making it a leading cause of disability. Human genome sequence data now permits the identification of specific genes associated with each aneusomy, the correlation of these genes with specific phenotypes, and ultimately therapeutic options. Toward this end, we have established and sustained a large multidisciplinary team: The Chromosome 18 Clinical Research Center. Herein, we propose a model for identifying the specific gene(s) associated with each phenotypic feature of 18q deletions (dosage sensitive genes). The model may be widely applicable to other chromosome abnormalities. Deletions of 18q are among the most common of the chromosome abnormalities, yet no dosage sensitive genes have been identified whose hemizygosity results in haploinsufficiency and therefore a phenotype. Our goal is to identify dosage sensitive genes on 18q and to characterize the clinical consequences of this hemizygosity. Building on our extensive experience with the chromosome 18 syndromes, we propose to correlate specific key phenotypic features (dysmyelination, growth hormone deficiency, atretic/stenotic ear canals, autism, cleft palate, and severe developmental delay) with the deletion of particular regions of chromosome 18q (critical region). To further narrow this critical region to a candidate gene (or genes), we will study karyotypically normal children with a specific phenotype (e.g., dysmyelination) and search for microdeletions in the previously identified critical region on chromosome 18. This strategy has already been used to identity a candidate gene responsible for the dysmyelination phenotype. Sequencing of the candidate gene in the phenotype specific population will identify additional individuals with chromosome 18q based disease. Then, the karyotypically normal child with chromosome 18q based disease will be clinically assessed to determine the spectrum of expressivity. This last step will initiate the process of comprehensively defining the phenotype resulting from deletion or mutation of an individual dosage sensitive gene. Furthermore, it will begin to piece together the genotypic components that combine to generate the full phenotype of a child with an 18q deletion.
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