Chromosomal microdeletions causing heart defects

染色体微缺失导致心脏缺陷

• 批准号: 8722001
• 负责人: JANET C KING
• 金额: $ 71.3万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722001
• 关键词: 1q44; 22q11; 22q11.22; 8q21; Adult; Affect; Bacterial Artificial Chromosomes; Biological Assay; Build-it; CRKL gene; California; Candidate Disease Gene; Cardiac Surgery procedures; Caring; Case-Control Studies; Cephalic; Child; Childhood; Chromosome Deletion; Chromosome Mapping; Chromosome abnormality; Chromosomes; Congenital Abnormality; Congenital Heart Defects; DNA Sequence; Defect; Development; Emotional; Etiology; Experimental Animal Model; Frequencies; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Grant; Heart; Human; Infant; Intervention; Investigation; Lead; Life; MAPK3 gene; Maps; Medical; Methods; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; National Heart, Lung, and Blood Institute; Neural Crest Cell; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; PTK2 gene; Parents; Pathway interactions; Phosphotransferases; Point Mutation; Population Study; Predisposition; Prevention strategy; Preventive; Preventive Intervention; Public Health; Recurrence; Regulatory Element; Research; Research Design; Research Personnel; Risk; Role; Sex Chromosomes; Signal Pathway; Signaling Pathway Gene; Single Nucleotide Polymorphism; Societies; Techniques; Testing; Tetralogy of Fallot; Variant; base; boys; cardiogenesis; clinical epidemiology; comparative; comparative genomic hybridization; dosage; economic cost; follow-up; genetic variant; genome wide association study; genome-wide; improved; infancy; innovation; insertion/deletion mutation; microdeletion; next generation; novel; population based; programs; reproductive; research clinical testing; research study

DESCRIPTION (provided by applicant): Conotruncal defects are clinically serious congenital heart malformations affecting the outflow tract of the developing heart. The etiologies of these conotruncal heart defects are largely unknown, but they are likely heterogeneous, involving environmental and genetic factors. The proposed research program will continue our focus on detecting genetic contributions to conotruncal heart defects. We have been supported by NHLBI R01 HL092330 to perform array comparative hybridization of 391 infants with conotruncal defects. We found that nearly 2% of boys with tetralogy of Fallot have an extra sex chromosome material. We have also successfully employed bacterial artificial chromosome array comparative genomic hybridization (array-CGH) to detect seven infants with novel submicroscopic chromosomal deletions involving chromosomes 22q11, 1q, and 10q23p and duplications of 8q21 and 8p23. Based on a novel microdeletion of the gene CRKL that we found by array-CGH, we will perform Next Generation DNA sequencing to identify mutations of genes of the signaling pathway FAK-CRKL-Erk1/Erk2 among 851 California infants with conotruncal heart defects. Murine experiments have shown that this pathway is an essential signaling pathway for cranial neural crest cells that migrate into the developing outflow tract of the heart. But there is almost nothing known about the potential contribution of sequence variation of the genes in this pathway to conotruncal defects in humans. We will also investigate three chromosomal regions where we found deletions and a duplication using array-CGH. We will use association studies of the three loci to narrow the candidate chromosomal regions. Then, we will turn to e Next Generation DNA sequencing again to identify mutations of candidate genes or regulatory elements that are located within the chromosomal microdeletions/duplication. The results of this research should lead to the development of more comprehensive, clinically applicable testing for children born with conotruncal heart defects. Our study populations of infants with conotruncal defects are unusually large and offer unique population-based investigations of children born with conotruncal defects. Overall, our 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.

描述（由申请方提供）：圆锥动脉干缺损是临床上严重的先天性心脏畸形，影响发育中心脏的流出道。这些圆锥动脉干心脏缺陷的病因在很大程度上是未知的，但它们可能是异质性的，涉及环境和遗传因素。拟议的研究计划将继续我们的重点是检测圆锥动脉干心脏缺陷的遗传贡献。我们得到了NHLBI R 01 HL 092330的支持，对391名圆锥动脉干缺陷的婴儿进行了阵列比较杂交。我们发现，近2%的法洛四联症男孩有一个额外的性染色体材料。我们还成功地采用细菌人工染色体阵列比较基因组杂交（阵列CGH）检测7名婴儿与新的亚显微染色体缺失涉及染色体22 q11，1 q和10 q23 p和重复的8 q21和8 p23。基于我们通过阵列CGH发现的CRKL基因的新微缺失，我们将进行下一代DNA测序，以确定851名加州圆锥动脉干心脏缺陷婴儿中FAK-CRKL-Erk 1/Erk 2信号通路基因的突变。小鼠实验表明，该途径是颅神经嵴细胞迁移到发育中的心脏流出道的重要信号传导途径。但几乎 目前还不知道该途径中基因序列变异对人类锥体干缺陷的潜在作用。我们还将研究三个染色体区域，我们发现缺失和重复使用阵列CGH。我们将使用三个位点的关联研究来缩小候选染色体区域。然后，我们将再次转向下一代DNA测序，以确定位于染色体微缺失/重复内的候选基因或调控元件的突变。这项研究的结果应该导致更全面的，临床适用的测试与圆锥动脉干先天性心脏缺陷的儿童的发展。我们研究的圆锥动脉干缺陷的婴儿人群非常大，并提供了独特的以人群为基础的圆锥动脉干缺陷儿童调查。总的来说，我们的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理解。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。

项目成果

Regulatory T Cells in Idiopathic Pulmonary Fibrosis: Too Much of a Good Thing?

特发性肺纤维化中的调节性 T 细胞：好事太多？

• DOI: 10.1016/j.ajpath.2016.06.002
• 发表时间: 2016
• 期刊: The American journal of pathology
• 作者: Moore,MeaganW;Herzog,EricaL
• 通讯作者: Herzog,EricaL

Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways.

• DOI: 10.1007/s00439-016-1727-x
• 发表时间: 2016-12
• 期刊: HUMAN GENETICS
• 影响因子: 5.3
• 作者: Hagen, Erin M.;Sicko, Robert J.;Kay, Denise M.;Rigler, Shannon L.;Dimopoulos, Aggeliki;Ahmad, Shabbir;Doleman, Margaret H.;Fan, Ruzong;Romitti, Paul A.;Browne, Marilyn L.;Caggana, Michele;Brody, Lawrence C.;Shaw, Gary M.;Jelliffe-Pawlowski, Laura L.;Mills, James L.
• 通讯作者: Mills, James L.