The genomic defect in familial amyotrophic lateral sclerosis (FALS) can be localized by analysis of DNA restriction fragment length polymorphisms (RFLPs) through establish linkage techniques. Two linkage methods are available: the sibpair methods of analysis and the standard likelihood linkage analysis. The sibpair method (of Elston and colleagues) is suitable as a screening technique in order to identify regional chromosomal localization, without assumptions concerning the mode of inheritance. The sibpair method generates no quantitative data for genetic counselling. Standard likelihood linkage can be used to verify linkage suggested by the sibpair method. The chromosomal location of several neurological diseases including Huntington's disease, myotonic dystrophy, and Duchenne muscular dystrophy has progressed so that major changes have occurred in the approach to patients and their families. Nineteen FALS families have been ascertained over the last three years. Additional families are available through collaboration with the University of Chicago and other institutions. DNA is currently available from 143 individuals banked as permanent lymphoblast cell lines. Continued development of the ascertained families is currently in progress. Preliminary results with seven RFLPs and 16 blood and serum markers have been analyzed. We plan to enlarge the data set for standard likelihood linkage analysis and sibpair analysis and to use highly polymorphic markers covering more than 90% of the human genome in a systematic analysis of this material. Identification of chromosomal localization using sibpair linkage will be confirmed by standard likelihood linkage and will be expanded using adjacent genetic markers. Once the neighborhood of a gene is determined, further studies to obtain tightly linked linkage markers that might be useful to identify the genetic locus will proceed.
