X Inactivation, Familial Skewed, 2

Description

In mammals, the potential imbalance of gene expression for the two X chromosomes in females is resolved by inactivating one X in all the somatic tissues. In the embryo proper, the process of X inactivation is believed 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.

See also SXI1 (300087), due to mutation in the XIST gene (314670) on chromosome Xq13.2.

Clinical Features

Naumova et al. (1998) analyzed X-chromosome inactivation patterns in lymphocytes of 264 females from 38 families not known to have any genetic disease. Quantitative measures of X inactivation showed strong sister-sister correlation in the degree of departure from equal numbers of cells having each X chromosome active, suggesting heritability of this phenotype. Strong sister-sister correlation was also observed for the fraction of cells having the same parent's X chromosome active, consistent with the possibility that this trait might be controlled by a cis-acting, X-linked gene. They used a sib-pair approach to determine whether X-inactivation phenotype was linked to loci in any region of the X chromosome.

Cau et al. (2006) reported a 4-generation family in which 6 of 8 females showed completely skewed X inactivation (ratio of 100:0) transmitted as an X-linked dominant trait. All affected women showing skewed X inactivation inherited the active X chromosome of their fathers. One of the woman had Lowe syndrome (309000) caused by a mutation in the OCRL1 (300535) gene in the paternally transmitted X chromosome. Analysis of the minimal XIST promoter showed normal sequence.

Renault et al. (2007) described a 3-generation Canadian family segregating 2 distinct phenotypes, hemophilia A (HEMA; 306700) and dramatically skewed X chromosome inactivation, the convergence of which led to the expression of the disorder in 3 heterozygous females. All affected males and females had a proximal (type II) IVS22 inversion of the F8 gene. No female carried more than 1 inverted allele. The 3 affected females had skewed X inactivation in favor of the mutant X; 3 unaffected females also had skewed X inactivation, 2 in favor of the normal X, and the third did not carry the mutation. Renault et al. (2007) stated that known causes of skewing were not consistent with their findings in this family, suggesting that the X chromosome inactivation ratios were genetically influenced.

Mapping

By quantitative and discrete measures of X-inactivation phenotype in women with skewed X inactivation, Naumova et al. (1998) found linkage to loci at chromosome Xq25-q26.

In a 4-generation family with skewed X inactivation, Cau et al. (2006) found linkage to a 3.4-cM region on chromosome Xq25 between markers DXS8067 and DXS8057 (parametric multipoint lod score of 2.11). Cau et al. (2006) noted that the region overlapped with that described by Naumova et al. (1998).

By linkage analysis of the X chromosome in a Canadian family with hemophilia A in which 3 affected females showed skewed X inactivation (Renault et al., 2007), Renault et al. (2011) found linkage to a 16.7-cM region on Xq25-q27, which overlaps by 0.7 cM with the region described by Naumova et al. (1998) and Cau et al. (2006). A region between DXS8098 and DXS8057 contains several genes, of which STAG2 (300826) was considered to be the most likely candidate. The analysis assumed a codominant model where homozygous females, regardless of genotype, tend toward balanced inactivation and heterozygosity results in skewed inactivation. No mutations were found in the STAG2 gene. The STAG2 gene, which is embryonically expressed, is a core component of the ring-like cohesin complex involved in sister chromatid cohesion during mitosis.