Homozygosity mapping of oculo-oto-facial dysplasia

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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.