Confirmation and refinement of the genetic localization of the Coffin-Lowry syndrome locus in Xp22.1-p22.2.

The Coffin-Lowry syndrome (CLS) is an X-linked inherited disease of unknown pathogenesis characterized by severe mental retardation, typical facial and digital anomalies, and progressive skeletal deformations. Our previous linkage analysis, based on four pedigrees with the disease, suggested a localization for the CLS locus in Xp22.1-p22.2, with the most likely position between the marker loci DXS41 and DXS43. We have now extended the study to 16 families by using seven RFLP marker loci spanning the Xp22.1-p22.2 region. Linkage has been established with five markers from this part of the X chromosome: DXS274 (lod score [Z] (theta) = 3.53 at theta = .08), DXS43 (Z(theta) = 3.16 at theta = .08), DXS197 (Z(theta) = 3.03 at theta = .05), DXS41 (Z(theta) = 2.89 at theta = .08), and DXS207 (Z(theta) = 2.73 at theta = .13). A multipoint linkage analysis further placed, with a maximum multipoint Z of 7.30, the mutation-causing CLS within a 7-cM interval defined by the cluster of tightly linked markers (DXS207-DXS43-DXS197) on the distal side and by DXS274 on the proximal side. Thus, these further linkage data confirm and refine the map location for the gene responsible for CLS in Xp22.1-p22.2. As no linkage heterogeneity was detected, this validates the use of the Xp22.1-p22.2 markers for carrier detection and prenatal diagnosis in CLS families.