FAMILIAL SKEWED-X INACTIVATION - A MOLECULAR TRAIT ASSOCIATED WITH HIGH SPONTANEOUS-ABORTION RATE MAPS TO XQ28

We report a family ascertained for molecular diagnosis of muscular dys trophy in a young girl, in which preferential activation (greater than or equal to 95% of cells) of the paternal X chromosome was seen in bo th the proband and her mother. To determine the molecular basis for sk ewed X inactivation, we studied X-inactivation patterns in peripheral blood and/or oral mucosal cells from 50 members of this family and fro m a cohort of normal females. We found excellent concordance between X -inactivation patterns in blood and oral mucosal cell nuclei in all fe males. Of the 50 female pedigree members studied, 16 showed preferenti al use (greater than or equal to 95% cells) of the paternal X chromoso me; none of 62 randomly selected females showed similarly skewed X ina ctivation (P <.0003). The trait for skewed X inactivation was maternal ly inherited in this family. A linkage study using the molecular trait of skewed X inactivation as the scored phenotype localized this trait to Xq28 (DXS1108; maximum LOD score [Z(max)] = 4.34, recombination fr action [theta] = 0). Both genotyping of additional markers and FISH of a YAC probe in Xq28 showed a deletion spanning from intron 22 of the factor VIII gene to DXS115-3. This deletion completely cosegregated wi th the trait (Z(max) = 6.92, theta = 0). Comparison of clinical findin gs between affected and unaffected females in the 50-member pedigree s howed a statistically significant increase in spontaneous-abortion rat e in the females carrying the trait (P <.02). To our knowledge, this i s the first gene-mapping study of abnormalities of X-inactivation patt erns and is the first association of a specific locus for recurrent sp ontaneous abortion in a cytogenetically normal family. The involvement of this locus in cell lethality, cell-growth disadvantage, developmen tal abnormalities, or the X-inactivation process is discussed.