The number of recognized brain malformations and syndromes has grown rapidly during the past several decades, yet relatively few causative genes have been identified, especially for three common malformations that have been associated with numerous cytogenetically visible chromosome deletions and duplications, and that often occur together: agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia (CVH) including Dandy-Walker malformation (DWM), and polymicrogyria (PMG). We propose to perform high-resolution array comparative genome hybridization (aCGH), emerging technology able to detect small copy number variants (CNV), in 700 probands with one or 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 of routine cytogenetic analysis, but detectable by current array platforms. We therefore expect to identify 70-100 patients with small CNV. We will distinguish CNV found in normal individuals from potentially disease-associated changes, and will confirm CNV using fluorescence in situ hybridization (FISH) and microsatellite (STRP) analysis. We will give highest priority to CNV that are de novo and involve 2 or more BACs, and secondary priority to familial and smaller CNV excluding known polymorphisms. After that, we will evaluate and rank candidate genes in the critical regions using information from public databases and our own expression studies, and perform mutation analysis of the best candidate genes from well-defined critical regions by sequencing in a large panel of subjects with phenotypes that match the phenotypes of the patients whose CNV define the critical regions. Here, we will use more refined criteria to supplement our clinical classification, such as the developmental level and presence of epilepsy or other birth defects. Any abnormalities found will be analyzed using existing data regarding polymorphisms (i.e. dbSNP), cross-species comparisons, and functional assays appropriate for the specific sequence change. We expect our focus on small chromosome imbalances to efficiently lead to discovery of new genes that cause these three focus malformations. These discoveries will lead directly to improved care for affected children and families consisting of more accurate diagnosis and outcome counseling, which will include specific diagnostic testing, 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 birth defects of the brain and related - but often less severe - developmental disorders. These results will prove immediately helpful in providing better information regarding diagnosis and prognosis to the families of affected children, and will also lead to better understanding of the underlying biology and in some cases to more effective treatment.
|Fregeau, Brieana; Kim, Bum Jun; HernÃ¡ndez-GarcÃa, AndrÃ©s et al. (2016) De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions. Am J Hum Genet 98:963-70|
|Hinkley, Leighton B N; Marco, Elysa J; Brown, Ethan G et al. (2016) The Contribution of the Corpus Callosum to Language Lateralization. J Neurosci 36:4522-33|
|Mirzaa, Ghayda M; Campbell, Catarina D; Solovieff, Nadia et al. (2016) Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol 73:836-45|
|Di Donato, Nataliya; Rump, Andreas; Mirzaa, Ghayda M et al. (2016) Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of ""PIK3CA-Related Overgrowth Spectrum"". Hum Mutat 37:242-5|
|Gobius, Ilan; Morcom, Laura; SuÃ¡rez, Rodrigo et al. (2016) Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum. Cell Rep 17:735-747|
|Mirzaa, Ghayda M; Conti, Valerio; Timms, Andrew E et al. (2015) Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. Lancet Neurol 14:1182-95|
|De Ciantis, A; Barkovich, A J; Cosottini, M et al. (2015) Ultra-high-field MR imaging in polymicrogyria and epilepsy. AJNR Am J Neuroradiol 36:309-16|
|Esmaeeli Nieh, Sahar; Madou, Maura R Z; Sirajuddin, Minhajuddin et al. (2015) De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann Clin Transl Neurol 2:623-35|
|Jansen, Laura A; Mirzaa, Ghayda M; Ishak, Gisele E et al. (2015) PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138:1613-28|
|Bassuk, Alexander G; Sherr, Elliott H (2015) A de novo mutation in PRICKLE1 in fetal agenesis of the corpus callosum and polymicrogyria. J Neurogenet 29:174-7|
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