Numerous human disorders arise from microdeletions and microduplications of relatively large genomic regions. These rearrangements can result in copy number alterations (CNAs) of one or more genes. Conditions arising from microdeletions and microduplications can manifest as multiple congenital anomalies (MCA) in patients. The most common phenotypic features observed in these patients include global developmental delay, mental retardation, cardiac defects and cranio-facial differences. Thus, diseases mediated by CNAs are referred to as 'genomic disorders'as large regions of the genome are altered leading to disorders in multiple organ systems. Many of the recurrent genomic disorders are mediated by aberrant homologous recombination between highly identical blocks of DNA sequences referred to as low copy repeats or segmental duplications (SDs) which may comprise up to 5% of the human genome. Despite this known correlation between SDs and genomic disorders, a significant proportion of SDs have not yet been associated with disease- causing genomic rearrangements. This observation suggests that other SD-mediated genomic disorders may exist but are currently undetectable mainly due to the low resolution of diagnostic techniques standardly used in molecular cytogenetics. We hypothesize that a significant proportion of children with MCA have a submicroscopic CNA that is not evident on standard genetic testing. We believe that a substantial number of these CNAs may be mediated by SDs or other unstable architecture within the human genome. We will test this hypothesis by analyzing patients with MCA using high resolution microarrays in order to detect disease-causing CNAs. Further, analysis of the genomic sequences at the rearrangement breakpoints will help determine what proportion of CNAs are mediated by predisposing genome architecture like SDs. The goal of this proposal is to identify previously undetectable, disease-causing CNAs in patients with MCA. The identification of genomic regions altered in MCA patients will allow a better understanding of the mechanisms underlying this group of disorders. We can then begin to assess the role of gene(s) in these regions that may be critical to early human developmental pathways. Relevance: Many children have genetic diseases that are undiagnosed due to limitations in current methods used for testing. These children may have very small deletions and duplications which can only be detected by techniques that allow a genomewide analysis. The identification of genomic regions that are deleted or duplicated in patients with birth defects will allow the identification of genes that are important in normal development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081519-03
Application #
7618666
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
2007-07-01
Project End
2009-11-30
Budget Start
2009-05-01
Budget End
2009-11-30
Support Year
3
Fiscal Year
2009
Total Cost
$184,581
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shaikh, Tamim H (2017) Copy Number Variation Disorders. Curr Genet Med Rep 5:183-190
Quintana, Anita M; Yu, Hung-Chun; Brebner, Alison et al. (2017) Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities. Hum Mol Genet 26:2838-2849
Coughlin 2nd, Curtis R; Scharer, Gunter H; Friederich, Marisa W et al. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet 52:532-40
Van Laarhoven, Peter M; Neitzel, Leif R; Quintana, Anita M et al. (2015) Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum Mol Genet 24:4443-53
Yu, Hung-Chun; Geiger, Elizabeth A; Medne, Livija et al. (2014) An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B. Am J Med Genet A 164A:950-7
Quintana, Anita M; Geiger, Elizabeth A; Achilly, Nate et al. (2014) Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression. Dev Biol 396:94-106
Yu, Hung-Chun; Sloan, Jennifer L; Scharer, Gunter et al. (2013) An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am J Hum Genet 93:506-14
Gai, X; Xie, H M; Perin, J C et al. (2012) Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry 17:402-11
Goldmuntz, Elizabeth; Paluru, Prasuna; Glessner, Joseph et al. (2011) Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies. Congenit Heart Dis 6:592-602
Shaikh, Tamim H; Haldeman-Englert, Chad; Geiger, Elizabeth A et al. (2011) Genes and biological processes commonly disrupted in rare and heterogeneous developmental delay syndromes. Hum Mol Genet 20:880-93

Showing the most recent 10 out of 23 publications