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.

No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

“…The absence of positive transmission results suggests that skewing is determined, at least in part, by post-XCI selection biases, some of which may be transmissible. Accordingly, a number of studies performed in non-neonatal populations have demonstrated a certain degree of heritability of skewing (65)(66)(67). In light of these considerations, we propose that neonatal skewing is caused in part, but not exclusively, by selection biases operating after primary XCI.…”

“…Skewing of XCI was also reported in rare cases of balanced X/autosome translocations, which perturbed the normal mechanisms of XCI (10). Furthermore, skewing has been associated with some complex traits such as recurrent abortion (11) and mental retardation (12), although the causative role of skewing in these situations has not been established. Skewing is a common feature of tumorigenic processes in which an acquired somatic mutation occurs in a single progenitor cell that subsequently undergoes clonal expansion and gives rise to progeny with the same XCI pattern (13,14).…”

“…Variant alleles of the X chromosome controlling element (Xce) were subsequently found to bias XCI in mice and cause skewing in heterozygous mice, suggesting that primary skewing was genetically controlled, at least in this species (31). In humans, no Xce-like element has been identified to date, though a few isolated reports have favored a genetic influence on primary skewing: (a) a rare mutation in the X (inactive)-specific transcript (XIST) minimal promoter was found to favor primary skewing (32,33); (b) an alteration in X chromosome inactivation center (XIC) was suggested to be responsible for the skewing of XCI observed in 3 related females (34); (c) twin studies reported a good concordance of XCI patterns between monozygous twins (35)(36)(37); and (d) other studies have documented the heritability of the skewing trait (38)(39)(40). Most of these studies either reported rare genetic events or were conducted in blood cells of adult females (likely affected by age-associated skewing).…”

X-inactivation analysis in the 1990s: promise and potential problems

“…They further demonstrated that affected individuals have a large segment of DNA deleted in the Xq28 region. 49 Further evidence for a genetic cause of NRXI came with the recent work by Plenge et al 50 who documented a rare cytosine to guanine mutation in the XIST (X-inactivation specific transcript) minimal promoter in nine females of two different families that all showed preferential inactivation of the X chromosome carrying the mutation.…”

“…These results suggested an X-linked transmission of NRXI in this family. Pegoraro et al 49 reported a high incidence of NRXI in a family and localized the genetic anomaly responsible for the trait to the Xq28 region using linkage analysis. They further demonstrated that affected individuals have a large segment of DNA deleted in the Xq28 region.…”