This unit describes the two approaches for molecular genetic diagnosis, direct mutation analysis and linkage studies. Direct mutation analysis is possible if the gene responsible for a disorder has been cloned and techniques exist to detect mutations. Genetic linkage analysis is used when polymorphic markers are available that are closely linked to a disease gene but the gene itself has not been cloned, or when it is difficult or impossible to detect mutations in the gene. For direct mutation analysis, the unit offers a review of the types of mutations that can be detected and the strategies that can be employed for their detection. The unit then describes the types of disorders that are best suited for linkage-based analysis and offers guidance for interpreting the data.