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%。尽管心脏流出道畸形和大动脉起源代表了先天性心脏病的一些最严重的形式，但人们对指导心脏流出道发育的正常分子信号或途径知之甚少，也不知道这些过程是如何以及为何发生的。有时会失败。过去 30 年，这些异常的手术矫正取得了重大进展，部分但并非所有 TOF 患者的临床结果、生殖健康和长期生存得到了显着改善（参见项目 1 和 2 进行讨论）。临床结果的这个范围是否反映了 TOF 的不同原因尚不清楚。分子遗传学分析已确定约 25% TOF 病例的遗传病因（单基因缺陷和/或细胞遗传学异常）。我们假设大多数 TOF 病例是由未识别的单基因突变引起的。该项目的中心主题是定义导致 TOF 的基因突变谱。 TOF 在家族中复发的发生率意味着 TOF 遗传学可能很复杂：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外显率，如 NKX2.5 或 TBX5 突变中发生的情况。其他 TOF 病例可能反映隐性突变。发育中心肌的新生种系突变和/或体细胞突变可能进一步导致非家族性 TOF 病例。我们的提案提出了几种定义 TOF 疾病基因的新方法，并将这些信息整合到其他 SCCOR 项目的数据中，以改善 TOF 的临床结果。具体来说，我们建议： 1. 分析已知的 TOF 疾病基因（JAG1、TBX1、TBX5、NKX2.5、FOX2 等）的突变，以建立基因型/表型关系并识别患有不明原因 TOF 的个体。 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. 通过对人类 RV 组织进行 SAGE 分析，识别潜在的新型 TOF 基因。 4. 筛选不明原因家族性 TOF 先证者中种系突变的候选基因以及非家族性 TOF 不明原因先证者中体细胞突变的候选基因。 5. 确定家系中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。