Chromosomal microdeletions causing heart defects

圆锥状心脏缺陷是严重的危及生命的畸形，其治疗需要大量的临床和手术干预，从童年到成年。但是圆锥状心脏缺陷的原因在很大程度上是未知的。拟议的研究计划将集中于检测两种最常见的圆锥锥体缺陷，法洛四联症和大动脉d转位的遗传贡献。利用细菌人工染色体（BAC）克隆的阵列比较基因组杂交（array- cgh）的最新发展将使我们能够采用这种高分辨率的全基因组筛选技术来检测亚微观染色体失衡。我们建议通过使用32,000克隆BAC阵列进行阵列- cgh来识别圆锥状心脏缺陷婴儿中的新生和家族性染色体微缺失。我们鉴定的微缺失将为我们提供相对较小的染色体区域，从中鉴定锥体缺陷的候选基因。我们还将设计和应用多重结扎依赖探针扩增（MLPA）检测来识别已知的锥体缺陷候选基因的单倍不足。这项研究的结果将导致全面的、临床适用的MLPA检测的发展，以检测所有圆锥状心脏缺陷基因及其外显子的拷贝数变化。我们为期两年的研究计划将使用最近完成的一项基于人群的病例对照研究的数据，该研究由1999年至2004年间出生的500名患有法洛四联症和d型大动脉转位的加利福尼亚婴儿组成。这是最大的婴儿锥体缺陷病例对照研究，将独特地产生锥体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锥体缺陷的遗传原因的科学理解。由于圆锥锥体缺陷导致大量发病率，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导致预防性干预措施，这将极大地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.