Homozygosity mapping of oculo-oto-facial dysplasia

眼耳面部发育不良的纯合性作图

• 批准号: 7076836
• 负责人: ANNE V HING
• 金额: $ 6.69万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076836
• 关键词: Alaskan Native American; autosomal recessive trait; clinical research; congenital oral /facial /cranial defect; family genetics; gene mutation; genetic carriers; genetic mapping; genetic screening; hearing disorders; human genetic material tag; human subject; patient oriented research; respiratory disorder; single nucleotide polymorphism

DESCRIPTION (provided by applicant): The investigators describe four related Native Alaskan individuals from a geographically isolated community, with birth defects involving the bones of the face. Clinical features include lower eyelid coloboma, choanal atresia, orofacial clefting, malar and mandibular hypoplasia, and external ear malformation with hearing loss. Cranial imaging studies demonstrate a unique orbital abnormality. They propose that these individuals have inherited a novel autosomal recessive oculo-oto-facial dysplasia gene (OOFD). It is hypothesized that the affected individuals in this pedigree have inherited two copies of the same gene mutation from a common ancestor. Preliminary estimates suggest that the carrier frequency in this Native Alaskan population may be as high as one in twenty nine. This condition has significant infant morbidity and mortality secondary to choanal atresia, which causes breathing obstruction and requires emergency airway management. Furthermore, individuals have developed profound progressive hearing loss and have required multiple corrective craniofacial surgeries throughout childhood and adulthood. These complications and the inability of prenatal ultrasound to predict choanal atresia underscore the importance of developing carrier testing for this population. Identification of the gene locus and genetic mutation will facilitate identification of gene carriers within the population. The long-term goal of this project is to determine the molecular basis of OOFD. This will be achieved through identification of the gene locus using homozygosity mapping, and determination of the specific gene mutation in affected individuals. Such studies could ultimately lead to the development of a genetic screening test, and would increase our understanding of craniofacial development. The investigators propose a genome-wide scan using high-density single nucleotide polymorphisms to identify the OOFD gene locus in this pedigree.

描述（由申请人提供）：调查人员描述了来自地理孤立社区的四个相关的阿拉斯加人，涉及脸部骨骼的出生缺陷。 临床特征包括下眼睑coloboma，Choanal闭锁，口面裂，疟疾和下颌骨症以及听力损失的外耳畸形。 颅底成像研究表明了独特的轨道异常。 他们建议这些人遗传了一种新型的常染色体隐性骨膜骨骼性异常增生基因（OOFD）。 假设该谱系中受影响的个体从共同祖先继承了两个相同基因突变的副本。 初步估计表明，阿拉斯加本地人口中的载流频率可能高达二十九个。 这种情况具有choanal闭锁继发的婴儿发病率和死亡率，这会导致呼吸阻塞并需要紧急气道管理。 此外，个人已经产生了严重的渐进性听力损失，并且在整个儿童期和成年期都需要进行多次矫正颅面手术。 这些并发症以及产前超声预测Choanal闭锁的无能为力，强调了为该人群开发载体测试的重要性。 基因基因座和遗传突变的鉴定将有助于鉴定人群中的基因载体。 该项目的长期目标是确定OOFD的分子基础。 这将通过使用纯合性映射鉴定基因基因座，并确定受影响个体的特定基因突变。 这样的研究最终可能导致遗传筛查测试的发展，并增加我们对颅面发展的理解。 研究人员建议使用高密度的单核苷酸多态性进行全基因组扫描，以鉴定该血统中的OOFD基因基因座。