Cardiovascular malformations (CVM) are a common class of birth defects that are major contributors to infant mortality and cost of neonatal care. A large body of epidemiological data has established that genetic factors play a large role in the causes of CVM. An important group of genetic abnormalities, called genomic disorders, involve imbalances in chromosomal copy number - usually deletions or duplications involving one or a few adjacent genes. Submicroscopic chromosomal imbalances have already been found to be important in several common complex or syndromic forms of CVM. These disorders are most likely to be observed in patients affected with CVM plus multiple congenital anomalies (MCA), but only approximately 10% of such cases have a known genomic disorder. Until recently, it has not been technically feasible to comprehensively survey the genome for such imbalances. In preliminary studies we have used several newly available microarray platforms to establish protocols for genome-wide survey of alterations in chromosomal copy number. In a feasibility study we found that about one third of CVM/MCA cases have relatively large submicroscopic chromosomal aberrations. In this research program, we propose to expand the copy number analysis of CVM/MCA cases. The results will allow more precise assessment of the frequency of pathological variants and to better characterize how they play a causal role in CVM. We propose to characterize the boundaries of the chromosomal imbalance events and to investigate the potential molecular mechanisms of gene dysfunction. We will prioritize individual genes that might play a direct role in the CVM phenotype and then examine whether more subtle mutations in those genes play a role in isolated or non-syndromic CVM. Identification of specific genes that underlie CVM would improve understanding of the origins of these common anomalies. Improved ability to screen for chromosomal imbalances and mutations in relevant genes will aid in diagnosis and early intervention for CVM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091771-04
Application #
8019545
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Schramm, Charlene A
Project Start
2008-02-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$383,750
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Prakash, Siddharth K; Bondy, Carolyn A; Maslen, Cheryl L et al. (2016) Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry. Am J Med Genet A 170:3157-3164
Prakash, Siddharth; Kuang, Shao-Qing; GenTAC Registry Investigators et al. (2016) Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections. PLoS One 11:e0153543
Probst, F J; James, R A; Burrage, L C et al. (2015) De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations. Orphanet J Rare Dis 10:75
Lalani, Seema R; Belmont, John W (2014) Genetic basis of congenital cardiovascular malformations. Eur J Med Genet 57:402-13
Lalani, Seema R; Shaw, Chad; Wang, Xueqing et al. (2013) Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur J Hum Genet 21:173-81
Wiszniewski, Wojciech; Hunter, Jill V; Hanchard, Neil A et al. (2013) TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. Am J Hum Genet 93:197-210
Lalani, Seema R; Ware, Stephanie M; Wang, Xueqing et al. (2013) MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development. Hum Mol Genet 22:4339-48
Marian, A J; Belmont, John (2011) Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res 108:1252-69
Lalani, S R; Thakuria, J V; Cox, G F et al. (2009) 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet 46:168-75
Yan, J; Zhang, F; Brundage, E et al. (2009) Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange. J Med Genet 46:626-34

Showing the most recent 10 out of 15 publications