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.

先天性心脏病影响大约 1% 的婴儿，估计死产的发病率接近十倍。心脏缺陷既被视为孤立的发现，又被视为综合征的组成部分。一些染色体综合征包括心脏缺陷作为表型的一致部分。此类综合征的例子包括唐氏综合征（AV 管缺陷）、DiGeorge/velocardiofacial（圆锥动脉干缺陷）、Williams 综合征（瓣膜上主动脉狭窄、肺血管受累）和 Alagille 综合征（肺动脉缺陷）。识别与这些和其他相关的特定基因 复杂的发育障碍有助于我们了解心脏发育中涉及的分子过程。人类端粒和亚端粒具有独特的结构，由多类 DNA 序列重复以及单拷贝序列组成。这些独特的序列区域基因丰富，容易断裂和重排。这种染色体断裂的后果已被证明会导致人类疾病。开发允许完整性分析的分子探针组 最近，使用荧光原位杂交 (FISH) 技术对亚端粒区域进行分析，促进了此类染色体重排患者的临床诊断。通过使用此测试，我们已经鉴定了 40 多个亚端粒重排病例。这些人中有百分之二十五患有先天性心脏病。我们已经开始对这些病例中的缺失边界进行分子表征，并一致发现先天性心脏缺陷（特别是与房间隔缺损和肺动脉异常相关的 6p 染色体，以及与圆锥干缺陷相关的 9q 染色体）。我们建议研究一组患有亚端粒重排和先天性心脏缺陷的患者，描述他们的缺失边界，并识别这些缺失中在突变时导致心脏缺陷的基因。我们假设这些研究将导致识别负责正常心脏发育的基因，这些基因突变后将导致综合征型和孤立型先天性心脏缺陷。