The number of recognized brain malformations and syndromes has grown rapidlyduring the past several decades, yet relatively few causative genes have been identified,especially for three common malformations that have been associated with numerouscytogenetically visible chromosome deletions and duplications, and that often occurtogether: agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia (CVH)including Dandy-Walker malformation (DWM), and polymicrogyria (PMG). We proposeto perform high-resolution array comparative genome hybridization (aCGH), emergingtechnology able to detect small copy number variants (CNV), in 700 probands with oneor more of these three malformations. Our central hypothesis states that more than 10%of patients with ACC, CVH or PMG will have de novo CNV below the resolution ofroutine cytogenetic analysis, but detectable by current array platforms. We thereforeexpect to identify 70-100 patients with small CNV. We will distinguish CNV found innormal individuals from potentially disease-associated changes, and will confirm CNVusing fluorescence in situ hybridization (FISH) and microsatellite (STRP) analysis. Wewill give highest priority to CNV that are de novo and involve 2 or more BACs, andsecondary priority to familial and smaller CNV excluding known polymorphisms. Afterthat, we will evaluate and rank candidate genes in the critical regions using informationfrom public databases and our own expression studies, and perform mutation analysis ofthe best candidate genes from well-defined critical regions by sequencing in a largepanel of subjects with phenotypes that match the phenotypes of the patients whose CNVdefine the critical regions. Here, we will use more refined criteria to supplement ourclinical classification, such as the developmental level and presence of epilepsy or otherbirth defects. Any abnormalities found will be analyzed using existing data regardingpolymorphisms (i.e. dbSNP), cross-species comparisons, and functional assaysappropriate for the specific sequence change. We expect our focus on small chromosome imbalances to efficiently lead todiscovery of new genes that cause these three focus malformations. These discoverieswill lead directly to improved care for affected children and families consisting of moreaccurate diagnosis and outcome counseling, which will include specific diagnostictesting, as well as improved genetic counseling.
The work proposed in this grant will lead to lead to the discovery of many of the genes that cause of birthdefects of the brain and related - but often less severe - developmental disorders. These results will proveimmediately helpful in providing better information regarding diagnosis and prognosis to the families of affectedchildren, and will also lead to better understanding of the underlying biology and in some cases to moreeffective treatment.
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