Familial Skewed X Inactivation: A Molecular Trait Associated with High Spontaneous-Abortion Rate Maps to Xq28

SummaryWe report a family ascertained for molecular diagnosis of muscular dystrophy in a young girl, in which preferential activation (≥ 95% of cells) of the paternal X chromosome was seen in both the proband and her mother. To determine the molecular basis for skewed X inactivation, we studied X-inactivation patterns in peripheral blood and/or oral mucosal cells from 50 members of this family and from a cohort of normal females. We found excellent concordance between X-inactivation patterns in blood and oral mucosal cell nuclei in all females. Of the 50 female pedigree members studied, 16 showed preferential use (≥ 95% cells) of the paternal X chromosome; none of 62 randomly selected females showed similarly skewed X inactivation (P < .0003). The trait for skewed X inactivation was maternally inherited in this family. A linkage study using the molecular trait of skewed X inactivation as the scored pheno-type localized this trait to Xq28 (DXS1108; maximum LOD score [Zmax] = 4.34, recombination fraction [θ] = 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 with the trait (Zmax = 6.92, θ = 0). Comparison of clinical findings between affected and unaffected females in the 50-member pedigree showed a statistically significant increase in spontaneous-abortion rate in the females carrying the trait (P < .02). To our knowledge, this is the first gene-mapping study of abnormalities of X-inactivation patterns and is the first association of a specific locus for recurrent spontaneous abortion in a cytogenetically normal family. The involvement of this locus in cell lethality, cell-growth disadvantage, developmental abnormalities, or the X-inactivation process is discussed