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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058721-06
Application #
8214639
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (05))
Program Officer
Morris, Jill A
Project Start
2008-03-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$825,147
Indirect Cost
$141,764
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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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
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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
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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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