Homozygosity mapping of oculo-oto-facial dysplasia

眼耳面部发育不良的纯合性作图

• 批准号: 6962738
• 负责人: ANNE V HING
• 金额: $ 6.59万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962738
• 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一个地理上与世隔绝的社区的四个相关的阿拉斯加原住民，他们的出生缺陷涉及面部骨骼。临床特征包括下睑缺损、后鼻孔闭锁、口裂、颧骨和下颌发育不良，以及伴有听力损失的外耳畸形。头颅影像检查显示一种独特的眼眶异常。他们认为这些人遗传了一种新的常染色体隐性遗传性眼耳面部发育不良基因(OOFD)。据推测，该家系中受影响的个体从共同的祖先那里继承了相同基因突变的两个副本。初步估计，这个阿拉斯加原住民的载频可能高达二十九分之一。这种情况有很高的婴儿发病率和死亡率，继发于后鼻孔闭锁，导致呼吸障碍，需要紧急呼吸道治疗。此外，个人已经发展成严重的进行性听力损失，并需要在整个童年和成年期间进行多次矫正颅面手术。这些并发症和产前超声无法预测后鼻孔闭锁，强调了为这一人群开展携带者检测的重要性。基因位点和基因突变的识别将有助于识别种群中的基因携带者。 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图谱识别基因位点，并确定受影响个体的特定基因突变来实现。这样的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了解。研究人员建议使用高密度单核苷酸多态进行全基因组扫描，以确定该家系中的OOFD基因位点。