Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54)

Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. A large genetic interval of assignment obtained on individual families by linkage analysis, genetic, heterogeneity, and phenotypic variability usually are major obstacles to fine-map and identify the related disease genes. Here we report on a large Tunisian family (MRX54) with an MRX condition. X-linked recessive inheritance is strongly suggested by the segregation of MR through seven unaffected carrier females to 14 affected males in two generations. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses. Recombinant events observed with the flanking markers DXS989 and DXS1218 delineate a refined locus of approximately 2.7 cM in accordance with the physical distance between these two markers. The small interval of assignment observed in this family overlaps not only with nine large MRX loci previously reported in Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in nonspecific MR. Although the involvement of several genes located in the Xp21.3-22.1 region cannot be ruled out, data reported in this study could be used as a starting point for the search of such gene(s).