Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28 - PubMed (original) (raw)

Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28

E Pegoraro et al. Am J Hum Genet. 1997 Jul.

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.

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Comment in

• Familial skewed X inactivation and X-linked mutations: unbalanced X inactivation is a powerful means to ascertain X-linked genes that affect cell proliferation.
  Migeon BR, Haisley-Royster C. Migeon BR, et al. Am J Hum Genet. 1998 Jun;62(6):1555-7; author reply 1557-8. doi: 10.1086/301858. Am J Hum Genet. 1998. PMID: 9585586 Free PMC article. No abstract available.

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