MOLECULAR GENETICS OF HUMAN SKELETAL DYSPLASIAS

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This study is designed to identify disease genes causing a variety of human skeletal dysplasias, including but not limited to the Ellis-van Creveld syndrome, proximal and distal symphalangism, and the nail-patella syndrome. Progress since April 1994 has included: 1) Ellis van Creveld (EvC) syndrome: A total of 110 markers spanning the human genome has been tested for linkage to the EvC phenotype in a large Amish pedigree from Lancaster County, Pennsylvania. To date, no definitive evidence for linkage has been achieved. These studies are continuing with additional markers placed more closely along the human gene map. It may be that the number of DNA samples of available to us for study is inadequate for the identification of linkage at the present time if this turns out to be the case, a major effort will be devoted to the identification and ascertainment of additional cases and families. 2) Proximal symphalangism. Linkage was found between PS phenotype and markers on chromosome 17q in a large Virginia family originally reported by Harvey Cushing in 1901. We have extended the pedigree from the original reports and from a follow-up study performed in 1964. An anonymous genome search was initiated resulting in the identification of markers on chromosome 17q linked to the PS phenotype with a maximum lod score of 5.94 at theta=0.2. 3) Nail-patella syndrome. Previous studies in our laboratory have shown that AK1, the gene encoding adenylate kinase-1 on chromosome 9q34, is the most closely linked marker to NPS in a large Mormon family segregating the disease. Linkage to AK1 has been recognized for three decades, as a result of linkage studies employing protein polymorphisms in the mid 1960s.