Molecular Analysis of Human Subtelomeric Rearrangements

人类亚端粒重排的分子分析

• 批准号: 7354822
• 负责人: IAN D. KRANTZ
• 金额: $ 34.29万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354822
• 关键词: 10p; Affect; Alagille Syndrome; Atrial Heart Septal Defects; Biological Assay; Blood Vessels; Candidate Disease Gene; Cardiac; Chromosomal Rearrangement; Chromosome Breakage; Chromosome Deletion; Chromosomes; Class; Clinical; Collaborations; Complex; Congenital Heart Defects; Country; Cytogenetic Analysis; Cytogenetics; DNA; DNA Markers; DNA Sequence; DNA Sequence Rearrangement; Data; Databases; Defect; Development; Diagnosis; Diagnostic; Down Syndrome; Embryo; Fluorescent in Situ Hybridization; G-Banding; Genes; Goals; Human; Incidence; Individual; Infant; Laboratories; Lead; Lung; Maps; Microsatellite Repeats; Molecular; Molecular Analysis; Molecular Cytogenetics; Molecular Probes; Mus; Mutate; Mutation; P1 Bacteriophage Artificial Chromosomes; Parents; Patients; Pattern; Pediatric Hospitals; Phenotype; Philadelphia; Process; Pulmonary artery structure; RNA; Research Personnel; Resolution; Resources; Sampling; Source; Standards of Weights and Measures; Structure; Supravalvular aortic stenosis; Syndrome; Technology; Testing; Time; Upper arm; Williams Syndrome; Xenopus; base; cisplatin/cyclophosphamide/doxorubicin protocol; clinical Diagnosis; clinical phenotype; cohort; congenital heart disorder; developmental disease; human disease; lymphoblastoid cell line; proband; size; stillbirth; telomere

Congenital heart disease affects approximately 1% of infants, with an incidence estimated at close to ten times that level among stillbirths. Heart defects are seen both as isolated findings and components of syndromes. Several chromosomal syndromes include heart defects as consistent parts of the phenotype. Examples of such syndromes include Down syndrome (AV canal defects), DiGeorge/velocardiofacial (conotruncal defects), Williams syndrome (supravalvular aortic stenosis, pulmonary vascular involvement), and Alagille syndrome (pulmonary artery defects). Identifying the specific genes involved in these and other complex developmental disorders have contributed to our understanding of the molecular processes involved in cardiac development. Human telomeres and subtelomeres have a unique structure consisting of multiple classes of DNA sequence repeats, as well as single copy sequences. These unique sequence regions are highly gene rich and prone to breakage and rearrangement. Consequences of this chromosome breakage have been shown to result in human disease. The development of molecular probe sets that permit the analysis of the integrity of the subtelomeric regions using fluorescence in situ hybridization (FISH) technology has recently advanced the clinical diagnosis of patients with these types of chromosomal rearrangements. Through the use of this testing we have identified over 40 cases of subtelomeric rearrangements. Twenty-five percent of these individuals have congenital heart defects. We have begun to molecularly characterize the deletion boundaries in those cases with a consistent finding of congenital heart defects (specifically chromosome 6p associated with atrial septal defects and pulmonary artery abnormalities, and 9q associated with conotruncal defects). We propose to study a cohort of patients with subtelomeric rearrangements and congenital heart defects, characterize their deletion boundaries, and identify genes within these deletions that are responsible for cardiac defects when mutated. We hypothesize that these studies will lead to the identification of genes responsible for normal cardiac development that when mutated will be responsible for both syndromic and isolated forms of congenital heart defects.

先天性心脏病会影响大约1％的婴儿，估计死亡人数的十倍。心脏缺陷既被视为孤立的发现和综合征的成分。几种染色体综合征将心脏缺陷作为表型的一致部分。这种综合症的例子包括唐氏综合症（AV管缺损），digeorge/velocardiofacial（conotruncal缺陷），威廉姆斯综合征（上毛促性狭窄，肺血管受累）和阿拉吉尔综合征（肺部动脉缺陷）。识别这些和其他涉及的特定基因 复杂的发育障碍有助于我们理解心脏发育所涉及的分子过程。人类端粒和亚电 - 具有独特的结构，该结构由多种DNA序列重复序列以及单复制序列组成。这些独特的序列区域非常富含基因，容易破裂和重排。这种染色体破裂的后果已显示出导致人类疾病。分子探针集的发展，允许对完整性进行分析 使用荧光原位杂交（FISH）技术的亚电体区域最近对这些类型的染色体重排患者进行了临床诊断。通过使用此测试，我们确定了超过40例亚电体重排。这些人中有25％患有先天性心脏缺陷。在那些情况下，我们已经开始分子表征缺失边界，并始终发现先天性心脏缺陷（特别是与心房缺陷和肺动脉缺陷相关的6P染色体6p，而9Q与综合骨骼的缺陷相关）。我们建议研究一群具有亚电体重排和先天性心脏缺陷的患者，表征其缺失边界，并在这些缺失中识别基因，这些基因在突变时导致心脏缺陷。我们假设这些研究将导致对正常心脏发育的基因鉴定，而当突变后，将是综合症和孤立形式的先天性心脏缺陷。