X-linked mental retardation (XLMR) constitutes a major cause of mental retardation in males. Although significant progress has been made in the last decade in understanding the Fragile X, little is known of the remaining X-linked disorders which collectively cause 60-70% of XLMR. Although 27 entities are documented in the present proposal, most families with XLMR remain without a specific diagnosis. Although suggestive X- chromosomal localizations have been reported for a few of these disorders in only one instance has the lod score reached significance. In general, direct laboratory diagnosis or prenatal diagnosis is not available for these families. The present investigation is designed to ascertain families with X-linked mental retardation (excluding Fragile X families), and to map as many of these disorders as possible using DNA probes and high resolution chromosome studies. This study will, therefore, contribute significantly to the linkage map of the X chromosome. Improved prenatal diagnosis for many of these disorders will also be a likely outcome. It is also designed to determine whether certain of these clinical descriptions in fact, represent the same disorder, and whether unusual genetic mechanisms are operative in this group of families. A combination of clinical, neuropsychological, MR imaging, and other studies will be utilized to further define the clinical and behavioral phenotypes of these disorders. Overall, the study is planned to ascertain and characterize 40-45 families in 5 years.