title: Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28.
abstract: We report a family ascertained for molecular diagnosis of muscular dystrophy in a young girl, in which preferential activation (> or = 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 (> or = 95% cells) of the paternal X chromosome; none of 62 randomly selected females showed similarly skewed X inactivation was maternally 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 [Zmax] = 4.34, recombination fraction [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 with the trait (Zmax = 6.92, theta = 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.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: J
authors.initials: J
authors.lastname: Whitaker
authors.forename: P
authors.initials: P
authors.lastname: Mowery-Rushton
authors.forename: U
authors.initials: U
authors.lastname: Surti
authors.forename: M
authors.initials: M
authors.lastname: Lanasa
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010375:Pedigree; D011247:Pregnancy; D014960:X Chromosome