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）：研究人员描述了来自地理上孤立的社区的四个相关的阿拉斯加原住民个体，他们的面部骨骼存在出生缺陷。 临床特征包括下眼睑缺损、后鼻孔闭锁、口面裂、颧骨和下颌骨发育不全、外耳畸形伴听力丧失。 头颅影像学研究显示一种独特的眼眶异常。 他们提出，这些个体遗传了一种新的常染色体隐性眼-眼-面发育不良基因（OOFD）。 据推测，该家系中受影响的个体从共同祖先遗传了两个相同基因突变的拷贝。 初步估计表明，阿拉斯加土著人口中的携带者频率可能高达二十九分之一。 这种情况有显着的婴儿发病率和死亡率继发于后鼻孔闭锁，这会导致呼吸阻塞，需要紧急气道管理。 此外，个体已经发展出严重的进行性听力损失，并且在整个童年和成年期需要多次矫正颅面手术。 这些并发症和产前超声无法预测后鼻孔闭锁强调了开发该人群的载体检测的重要性。 基因位点和基因突变的识别将有助于识别人群中的基因携带者。 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作图鉴定基因位点和确定受影响个体的特定基因突变来实现。 这些研究最终可能导致基因筛查测试的发展，并将增加我们对颅面发育的理解。 研究人员提出了一个全基因组扫描使用高密度单核苷酸多态性，以确定该家系的OOFD基因位点。