X Inactivation, Familial Skewed, 1

A number sign (#) is used with this entry because of evidence that familial skewed X inactivation-1 (SKI1) is caused by mutation in the XIST gene (314670) on chromosome Xq13.

Description

In mammals, the potential imbalance of gene expression for the two X chromosomes in females is resolved by inactivating one X in all somatic tissues. In the embryo proper, the process of X inactivation is considered to be random between the maternal and paternal chromosomes. Thus, most females have mosaic expression of maternal and paternal alleles of X chromosome loci, with a contribution of about 50% from each chromosome. However, some females show a skewed ratio of X inactivation, which can be due to negative or positive selection, or to an underlying primary genetic process. Belmont (1996) observed familial clustering of females with highly skewed patterns of X inactivation and reviewed the genetic control of X inactivation.

Genetic Heterogeneity of Skewed X Inactivation

See also SXI2 (300179) for a locus that maps to chromosome Xq25-q26.

Clinical Features

Pegoraro et al. (1997) reported a family ascertained for molecular diagnosis of muscular dystrophy in a young girl, in which preferential activation (greater than 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, they studied X-inactivation patterns in peripheral blood and/or oral mucosal cells from 50 members of the family and from a cohort of normal females. In all females, they found excellent concordance between X-inactivation patterns in blood and oral mucosal cell nuclei. Of the 50 female pedigree members studied, 16 showed preferential use (greater than 95% of cells) of the paternal X chromosome; none of 62 randomly selected females showed similarly skewed X inactivation (p less than 0.0003). The trait for skewed X inactivation was maternally inherited in this family.

Naumova et al. (1996) had reported a family with familial skewed X inactivation with preferential use of the paternal X chromosome. This family was of insufficient size, however, to permit genetic mapping of the trait or to establish the pattern of inheritance.

Parolini et al. (1998) reported X-linked Wiskott-Aldrich syndrome (WAS; 301000) in an 8-year-old girl. She had a sporadic mutation in the WAS gene (300392), glu133 to lys, on the paternally derived X chromosome, but had nonrandom X inactivation of the maternal X chromosome in both blood and buccal mucosa. Her mother and maternal grandmother also had nonrandom X inactivation, which suggested to the authors the possibility of a defect in XIST (314670) or some other gene involved in the X-inactivation process. Puck and Willard (1998) commented on the subject of X inactivation in females with X-linked disease in reference to the paper by Parolini et al. (1998).

Other Features

Sangha et al. (1999) presented evidence that factors associated with extremely skewed X-chromosome inactivation account for a significant proportion (i.e., as much as 18%) of couples with recurrent spontaneous abortion. Lanasa et al. (1999) reported similar results for women who experienced 2 or more spontaneous abortions.

Hypothesizing that an association between highly skewed X-chromosome inactivation and recurrent spontaneous abortion would reflect an association with trisomic conception, Warburton et al. (2009) compared the distribution of X-chromosome inactivation skewing percentages among women with spontaneous abortions in 4 karyotype groups, including 154 with trisomy, 43 with chromosomally normal male, 38 with chromosomally normal female, and 61 with nontrisomic chromosomal abnormalities, to the distribution for 388 age-matched controls with chromosomally normal births. In secondary analyses, the authors subdivided the nontrisomic chromosomally abnormal group, divided trisomies by chromosome, and classified women by reproductive history. Warburton et al. (2009) found no association between highly skewed X-chromosome inactivation and trisomy, chromosomally normal male spontaneous abortions, or recurrent abortion.

Inheritance

Azofeifa et al. (1995) had presented evidence that skewed X inactivation may be an inherited molecular trait in some families.

The observation by Pegoraro et al. (1994) that more than 90% of isolated manifesting carriers of Duchenne muscular dystrophy (DMD; 310200) showed paternal inheritance of a new dystrophin-gene mutation (at 27-fold variance with Bayesian predictions) suggested an underlying genetic mechanism for skewed X inactivation.

Mapping

By linkage analysis of a family showing skewed X inactivation, Pegoraro et al. (1997) found linkage to chromosome Xq28 (maximum lod score of 4.34 at theta = 0.0 was observed with DXS1108). Both genotyping of additional markers and fluorescence in situ hybridization of a YAC probe from Xq28 showed a deletion spanning from intron 22 of the factor VIII gene (300841) to DXS115-3. This deletion completely cosegregated with the trait. Comparison of clinical findings between affected and unaffected females in the 50-member pedigree showed a statistically significant increase in the rate of spontaneous abortions in females carrying the trait (P less than 0.02).

To examine the heritability of the X-inactivation phenotype, Naumova et al. (1998) used a sib-pair approach in 264 females from 38 families. The analyses, which were largely independent of mode of inheritance, indicated that the X-chromosome inactivation phenotype is heritable and is linked to loci within or near the XIST gene at Xq13-q21 and at Xq25-q26. Presumably the determinant shown to be linked to XIST was the same as that identified by Plenge et al. (1997).

Molecular Genetics

Plenge et al. (1997) identified a mutation in the promoter region of the XIST gene (314670.0001) in multiple females in a family reported by Rupert et al. (1995) as showing nonrandom X-chromosome inactivation.