Chromosomal microdeletions causing heart defects

圆锥动脉干心脏缺陷是严重的危及生命的畸形，其治疗需要在整个儿童期和成年期进行大量的临床和外科干预。但圆锥动脉干心脏缺陷的原因在很大程度上是未知的。 拟议的研究计划将侧重于检测两种最常见的圆锥动脉干缺陷，法洛四联症和大动脉d型转位的遗传贡献。最近发展的阵列比较基因组杂交（阵列CGH）使用映射细菌人工染色体（BAC）克隆将使我们能够采用这种高分辨率，全基因组筛选技术来检测亚显微镜下的染色体不平衡。我们建议通过使用32，000个克隆BAC阵列进行阵列CGH来识别圆锥动脉干心脏缺陷婴儿中的新发和家族性染色体微缺失。微缺失，我们确定将为我们提供一个相对较小的染色体区域，从中确定候选基因的圆锥动脉干缺陷。我们还将设计和应用多重连接依赖性探针扩增（MLPA）检测，以确定单倍不足的已知候选基因的圆锥动脉干缺陷。这项研究的结果应导致全面的，临床适用的MLPA检测，将检测所有圆锥动脉干心脏缺陷基因及其外显子的拷贝数变化的发展。我们为期2年的研究计划将使用最近完成的基于人群的病例对照研究的数据，该研究包括1999年至2004年间出生的500名患有法洛四联症和d型大动脉转位的加州婴儿。这是对圆锥动脉干缺陷婴儿进行的最大规模的病例对照研究，并将唯一地生成关于圆锥动脉干缺陷候选基因的基于人群的基因型数据。总的来说，这项研究计划试图提高我们对圆锥动脉干缺陷遗传原因的科学认识。 由于圆锥动脉干缺陷会导致大量的发病率，以及高昂的情感和经济成本，扩大我们对其原因的了解可能会导致预防性干预措施，这将大大有利于公共卫生和社会。

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.