Conotruncal heart defects are severe life threatening malformations whose treatment requires substantial clinical and surgical interventions throughout childhood and into adult years. But the causes of conotruncal heart defects are largely unknown. The proposed research program will focus on detecting genetic contributions to the two most common conotruncal defects, tetralogy of Fallot and d-transposition of the great arteries. The recent development of array comparative genomic hybridization (array-CGH) using mapped bacterial artificial chromosome (BAC) clones will allow us to employ this high resolution, genome-wide screening technique to detect submicroscopic chromosomal imbalances. We propose to identify de novo and familial chromosomal microdeletions among infants with conotruncal heart defects by performing array-CGH with a 32,000 clone BAC array. The microdeletions that we identify will provide us with relatively small chromosomal regions from which to identify candidate genes for conotruncal defects. We will also design and apply multiplex ligation dependent probe amplification (MLPA) assays to identify haploinsufficiency of known candidate genes for conotruncal defects. The results of this research should lead to the development of comprehensive, clinically applicable MLPA assays that will detect copy number changes of all conotruncal heart defect genes and their exons. Our 2-year research program will use data from a recently completed population-based case-control study composed of 500 California infants with tetralogy of Fallot and d-transposition of the great arteries, delivered between 1999 and 2004. This is the largest case-control study of infants with conotruncal defects and will uniquely generate population-based genotypic data on candidate genes for conotruncal defects. Overall, this research program attempts to enhance our scientific understanding of the genetic causes of conotruncal defects. Because conotruncal defects result in substantial morbidity, as well as high emotional and economic costs, expanding our understanding of their causes may lead to preventive interventions that would greatly benefit public health and society.

Public Health Relevance

Conotruncal heart defects are cyanotic, life-threatening birth defects that are very costly to society and that require medical interventions through childhood and adulthood. Infants with conotruncal heart defects require major heart surgery during infancy, and frequently repeated surgical interventions. Almost nothing is known about the causes of conotruncal heart defects, but the frequency of familial recurrences strongly suggests there are genetic contributions. The objective of our research is identify submicroscopic chromosomal abnormalities that cause conotruncal heart defects, with a goal that improved understanding of causes may lead to better clinical testing to identify children with chromosomal microdeletions, which would then allow individualized preventive care for those children, allow more informed reproductive planning for their parents and the children, an hopefully, development of improved preventive strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Schramm, Charlene A
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Children's Hospital & Res Ctr at Oakland
United States
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Osoegawa, Kazutoyo; Iovannisci, David M; Lin, Bin et al. (2014) Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects. Am J Med Genet A 164A:397-406
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