Human Mutations that Cause Tetralogy of Fallot

导致法洛四联症的人类突变

• 批准号: 6772363
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 40.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772363
• 关键词: clinical research; congenital heart disorder; cytogenetics; developmental genetics; family genetics; gel electrophoresis; gene expression; gene mutation; genetic screening; genotype; heart ventricle; human subject; immunocytochemistry; microarray technology; myocardium; northern blottings; phenotype; polymerase chain reaction; serial analysis of gene expression; tetralogy of Fallot; western blottings

Tetralogy of Fallot (TOF) accounts for approximately 8-10% of congenital heart disease. Although malformations of the cardiac outflow tract and the origins of the great arteries represent some of the severest forms of congenital heart disease, little is known about the normal molecular signals or pathways that direct development of the cardiac outflow tract, nor how and why these processes sometimes fail. Major advances in surgical correction of these anomalies over the past 30 years have led to markedly improved clinical outcome, reproductive fitness and long-term survival in some but not all patients with TOF (see Projects 1 and 2 for discussion). Whether this range in clinical outcomes reflects different causes of TOF is unknown. Molecular genetic analyses have defined a genetic etiology in approximately 25% of TOF cases (single gene defects and/or cytogenetic abnormalities). We hypothesize that unidentified monogenic mutation accounts for most TOF cases. A central theme of this project is to define the spectrum of gene mutations that cause TOF. The incidence of TOF recurrence in families implies that the TOF genetics may be complex: some cases may be dominant, but exhibit variable expressivity and incomplete penetrance, as occurs in NKX2.5 or TBX5 mutations. Other TOF cases may reflect recessive mutations. De novo germline mutations and/or somatic mutation of the developing myocardium may further contribute to nonfamilial cases of TOF. Our proposal suggests several novel approaches to define TOF disease genes and to integrate this information into data derived from other SCCOR projects so as to improve clinical outcomes in TOF. Specifically we propose to: 1. Analyze known TOF disease genes (JAG1, TBX1, TBX5, NKX2.5, FOX2 and others) for mutations to establish genotype/phenotype relationships and to identify individuals with TOF of unknown cause. 2. Clinically evaluate family members of individuals with TOF of unknown cause to stratify probands and kindreds for further genetic studies. 3. Identify potential novel TOF genes through SAGE analyses of human RV tissues. 4. Screen candidate genes for germline mutations in probands with familial TOF of unknown cause and for somatic mutations in probands with nonfamilial TOF of unknown cause. 5. Identify the genetic basis for TOF and other congenital heart malformations in pedigrees appropriate for positional cloning techniques.

Fallot（TOF）的四部曲约占先天性心脏病的8-10％。尽管心脏流出道的畸形和大动脉的起源代表了先天性心脏病的某些最严重形式，但对直接发展心脏流出道的正常分子信号或途径知之甚少，或者这些过程有时如何以及为什么失败。在过去的30年中，这些异常的手术校正方面的重大进展导致一些有TOF的患者的临床结果，生殖健康和长期生存显着改善（有关讨论，请参见项目1和2）。临床结果中的这种范围是否反映了TOF的不同原因是未知的。分子遗传分析已定义了大约25％的TOF病例（单基因缺陷和/或细胞遗传学异常）的遗传病因。我们假设身份不明的单基因突变是大多数TOF病例。该项目的一个核心主题是定义引起TOF的基因突变的频谱。家族中TOF复发的发生率意味着TOF遗传学可能是复杂的：某些情况可能是主导的，但表现出可变的表现性和不完全的渗透率，如NKX2.5或TBX5突变所发生的那样。其他TOF病例可能反映了隐性突变。发育中心肌的从头种系突变和/或躯体突变可能进一步有助于TOF的非家族病例。我们的建议提出了几种定义TOF疾病基因的新方法，并将这些信息整合到来自其他SCCOR项目的数据中，以改善TOF的临床结果。具体而言，我们建议：1。分析已知的TOF疾病基因（JAG1，TBX1，TBX5，NKX2.5，FOX2等），以建立基因型/表型关系，并鉴定患有未知原因的人。 2。临床评估患有未知原因的人的家庭成员，以对进一步的遗传研究进行分层和亲属分层。 3。通过对人RV组织的鼠尾草分析来确定潜在的新型TOF基因。 4。筛查候选基因，用于未知原因的家族性TOF和具有未知原因的非家族TOF的概率中的家族性TOF和体细胞突变的筛查基因。 5。确定家谱中TOF和其他先天性心脏畸形的遗传基础 适用于位置克隆技术。