Homozygosity mapping of oculo-oto-facial dysplasia

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，他们都有面部骨骼的先天缺陷。临床特征包括下睑结瘤、后肛闭锁、口面裂、颧、下颌发育不全、外耳畸形伴听力丧失。颅成像研究显示一个独特的眶异常。他们提出这些个体遗传了一种新的常染色体隐性眼-耳-面部发育不良基因（OOFD）。据推测，在这个谱系中受影响的个体从一个共同的祖先那里继承了相同基因突变的两个拷贝。初步估计表明，在这个阿拉斯加土著人口中，携带频率可能高达29分之一。这种情况有显著的婴儿发病率和死亡率继发于后肛门闭锁，导致呼吸阻塞，需要紧急气道管理。此外，患有严重进行性听力损失的患者在儿童期和成年期需要进行多次颅面矫正手术。这些并发症和产前超声无法预测后肛门闭锁强调了对这一人群进行携带者检测的重要性。基因位点和基因突变的鉴定将有助于种群内基因携带者的鉴定。

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.