(taken from application) Facio-audio-symphalangism (FAS) is an autosomal dominant disorder characterized by a triad of findings including distinct facies, early onset deafness and progressive joint fusions. We have identified a large Hawaiian family with this disorder. The goal of this project is to define the phenotype and natural history of the disease, determine the chromosomal location of the defective gene and identify the defective gene. To this end, the specific aims of the proposal are: 1) To define the clinical phenotype and natural history of facio-audio-symphalangism. We will delineate the clinical and radiographic findings as well as the natural history of the disorder in this large, multigeneration family. 2) To determine the chromosomal location of the defective gene. Employing markers in both candidate genes and genome wide markers, I will use linkage studies to determine the chromosomal region containing the disease gene. 3) To determine if there is locus heterogeneity in facio-audio-symphalangism and if other phenotypically similar dominantly inherited disorders map to the same chromosomal location. By performing linkage analysis on other facio-audio-symphalangism families I will determine if there is more than one FAS disease gene. I will also carry out linkage studies in families with related disorders, including multiple synostoses syndrome and proximal symphalangism, to determine if the disease genes co-localize with FAS. 4) To identify the disease gene in facio-audio-symphalangism. By a positional strategy, candidate genes from the FAS interval will be isolated. Mutation analysis will be used to identify the defective gene in FAS. This project represents a genetic approach to dissecting the poorly understood process of the development and maintenance of joint integrity. Identification of a gene involved in this process will provide the means to identify other genes involved in this complex pathway and stimulate biologic research in this area.
| Krakow, D; Salazar, D; Wilcox, W R et al. (2000) Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes. Eur J Hum Genet 8:645-8 |
| Korkko, J; Cohn, D H; Ala-Kokko, L et al. (2000) Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. Am J Med Genet 92:95-100 |
| Gong, Y; Krakow, D; Marcelino, J et al. (1999) Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21:302-4 |
| Krakow, D; Reinker, K; Powell, B et al. (1998) Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22. Am J Hum Genet 63:120-4 |
