One of the major goals of the field of human genetics is to define the relationship between human genotype and phenotype. Much of our assessment of genotypic variation has been focused on small scale, single nucleotide events. Our understanding of the molecular basis of disease, however, has begun to reveal that large-scale differences including micro duplications and micro deletions contribute significantly to childhood disease, disease susceptibility and normal variation in the population. Despite its importance, there has been no systematic study of this form of genotypic variation. The long-term objective of this proposal is to investigate the pattern and nature of this large-scale variation. Our approach will be directed to regions of the genome that contain highly homologous duplicated sequence and therefore have an increased probability of genomic gain and loss. This proposal is a collaborative effort that brings together expertise in genome structure, array comparative genomic hybridization technology and mental retardation.
The specific aims of this proposal are (1) to identify and validate all intrachromosomally duplicated regions within the human genome, (2) to develop a set of large-insert clones bracketed by duplicated sequence to be placed on a CGH microarray platform for genome-wide screening, (3) to assess copy number variation within both normal individuals and children with idiopathic mental retardation and (4) to validate the extent, frequency and inheritance pattern of these large structural """"""""polymorphisms"""""""". This project aims to address two fundamental questions; what is the nature and frequency of duplication-mediated structural polymorphisms within the human genome? Are there an excess of de novo events among children with mental retardation and congenital birth defects? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD043569-01
Application #
6562016
Study Section
Special Emphasis Panel (ZRG1-GEN (02))
Program Officer
Oster-Granite, Mary Lou
Project Start
2003-01-03
Project End
2007-12-31
Budget Start
2003-01-03
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$517,858
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Girirajan, Santhosh; Eichler, Evan E (2010) Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 19:R176-87
de Kovel, Carolien G F; Trucks, Holger; Helbig, Ingo et al. (2010) Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133:23-32
Mefford, Heather C; Muhle, Hiltrud; Ostertag, Philipp et al. (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6:e1000962
Mefford, Heather C; Shafer, Neil; Antonacci, Francesca et al. (2010) Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis. Am J Med Genet A 152A:2203-10
Hannes, F D; Sharp, A J; Mefford, H C et al. (2009) Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46:223-32
Itsara, Andy; Cooper, Gregory M; Baker, Carl et al. (2009) Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 84:148-61
Helbig, Ingo; Mefford, Heather C; Sharp, Andrew J et al. (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41:160-2
Mefford, Heather C; Eichler, Evan E (2009) Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev 19:196-204
Mefford, Heather C; Cooper, Gregory M; Zerr, Troy et al. (2009) A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res 19:1579-85
Sharp, Andrew J; Mefford, Heather C; Li, Kelly et al. (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322-8

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