Chromosomal microdeletions causing heart defects

圆锥干心脏缺陷是一种严重威胁生命的畸形，其治疗需要在整个童年和成年期间进行大量的临床和手术干预。但圆锥干心脏畸形的原因在很大程度上尚不清楚。拟议的研究计划将专注于检测两种最常见的圆锥干畸形--法洛四联症和大动脉转位--的基因贡献。使用定位的细菌人工染色体(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使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个克隆BAC阵列进行阵列-CGH来识别患有圆锥干心脏缺陷的婴儿的从头开始的和家族性的染色体微缺失。我们识别的微缺失将为我们提供相对较小的染色体区域，从中识别圆锥干缺陷的候选基因。我们还将设计和应用多重连接依赖的探针扩增(MLPA)分析来识别圆锥干缺陷的已知候选基因的单倍性不足。这项研究的结果将导致开发全面的、临床适用的MLPA检测方法，该方法将检测所有圆锥干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，该研究包括500名患有法洛四联症和大动脉转位的加州婴儿，该研究在1999至2004年间进行。这是对患有圆锥干缺陷的婴儿进行的最大规模的病例对照研究，将独特地产生关于圆锥干缺陷候选基因的基于人群的基因分型数据。总体而言，这项研究计划试图加强我们对圆锥干缺陷遗传原因的科学理解。由于圆锥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理解可能会导致预防性干预，从而极大地造福公众健康和社会。

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.