This project is one of several which combine molecular and clinical studies of X-linked neuromuscular diseases. Traditional genetic analysis has begun with delineation of a phenotype which is then investigated for familial aggregation and pattern of inheritance; evidence for genetic heterogeneity is sought. Markers and protein studies attempt to move closer to the gene product. Based on recent advances in mapping of the human X chromosome, we propose to reverse this process. DNA genotyping in families in which an X-linked disorder is segregating allows independent identification of hemizygous and heterozygous carriers of the mutant gene. The results are compared with the pedigree and a blinded clinical evaluation of family members. This approach is uniquely applicable to heterozygous females for X-linked mutations where a single affected male identifies numerous females as potential heterozygotes. The wide variability in expression of X-linked disorders in females due to random inactivation of the X chromosome and incomplete penetrance often leads to the assumption of insignificant consequences of the disorder for heterozygous females. A large VA kindred with X-linked Charcot-Marie-Tooth disease (CMT-X) has been identified and shown to have a distinctive pattern of clinical and electrophysiological findings. DNA analysis by RFLP's has shown the family to be highly informative for a number of DNA markers which map to the proximal long arm of the X chromosome and to confirm the location of the CMT-X gene between the centromere and Xq13. This project will expand the DNA analysis in order to produce a more detailed genetic map of the CMT-X locus and surrounding DNA markers and gene loci. Further clinical assessment of the disorder will concentrate on the natural history of CMT-X in females. Efforts will be made to identify additional families with CMT-X; two additional families have been ascertained in VA and will be incorporated in these studies. Numerous colleagues have agreed to supply DNA samples from a single affected male of families known to them. In addition to further linkage studies, a panel of DNA samples from affected males will be established and used to search for deletional mutations resulting in CMT-X. Detection of such a deletion would more precisely map the gene locus and facilitate eventual cloning of the CMT-X locus. During the course of these studies, pedigree data and DNA samples from selected families with other forms of CMT will be collected for future mapping studies.
