The focus of this grant is to develop reliable topographic criteria for detecting subclinical forms of keratoconus to enable us to conduct critical pedigree analyses and delineate modes of inheritance of familial keratoconus. These data combined with cell lines established on the multiple keratoconus families ascertained will create a unique resource for future molecular genetic studies. 1,000 subjects(200 normals, 300 keratoconus probands and 500 keratoconus family members) will undergo ocular evaluation and videokeratography over a 5 year period to observe longitudinal clinical and topographic trends. The goal is to examine the relationship of videokeratography variables to biomicroscopic indicators - of disease status and develop criteria for 'mildly affected' (subclinical) keratoconus family members. Upon completion of the longitudinal analyses of study subjects and once criteria have been devised for identifying 'mildly affected' individuals, family data will be analyzed by complex segregation analysis techniques to determine the mode(s) of inheritance of the various definitions of the keratoconus phenotype. Establishing reliable criteria for 'mild' topographic phenotypes, critical for constructing accurate family pedigrees, will enable us to pursue a variety of molecular genetic linkage studies using permanent lymphoblastoid lines established on the many useful keratoconus family pedigrees ascertained thus far in this study. Identifying a gene or genes contributing to the pathogenesis of keratoconus may provide insights into devising medical therapy to arrest its progression and prevent the need for multiple contact lens changes and/or cornea transplantation in select individuals.