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.

法洛四联症（TOF）约占先天性心脏病的8-10%。虽然心脏流出道和大动脉起源的畸形是先天性心脏病最常见的形式之一，但对指导心脏流出道发育的正常分子信号或途径以及这些过程如何以及为什么有时会失败知之甚少。在过去的30年里，这些异常的手术矫正取得了重大进展，使一些但不是所有TOF患者的临床结局、生殖健康和长期生存率得到了显著改善（讨论见项目1和项目2）。临床结果的这一范围是否反映了TOF的不同原因尚不清楚。分子遗传学分析已经确定了约25% TOF病例的遗传病因（单基因缺陷和/或细胞遗传学异常）。我们推测，不明单基因突变占大多数TOF病例。该项目的一个中心主题是确定导致TOF的基因突变谱。TOF家族复发的发生率意味着TOF遗传学可能是复杂的：某些病例可能是显性的，但表现出可变的表达性和不完全的表达率，如NKX2.5或TBX 5突变。其他TOF病例可能反映隐性突变。新生胚系突变和/或发育中心肌的体细胞突变可能进一步导致TOF的非家族性病例。我们的建议提出了几种新的方法来定义TOF疾病基因，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（JAG 1、TBX 1、TBX 5、NKX2.5、FOX 2等）的突变，以建立基因型/表型关系，并识别未知原因的TOF个体。2.对不明原因TOF患者的家庭成员进行临床评估，对先证者和亲属进行分层，以进行进一步的遗传学研究。3.通过对人RV组织的SAGE分析鉴定潜在的新TOF基因。 4.在原因不明的家族性TOF先证者中筛选候选基因的种系突变，在原因不明的非家族性TOF先证者中筛选候选基因的体细胞突变。 5.在家系中确定TOF和其他先天性心脏畸形的遗传基础 适用于定位克隆技术。