ClinGen Dosage Sensitivity Curation Page

XIST

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
8265665 Migeon et al (1993) describe 8 females with small ring X chromosomes and a severe phenotype including intellectual disability. Seven had either absent XIST confirmed by FISH or a lack of RNA by RT-PCR. The remaining patient had two rings, one large ring with XIST present and one small ring with XIST absent by FISH. This lack of functional XIST prevented the ring chromosome from inactivating and led to a more severe phenotype than typically is seen in girls with Turner syndrome.
11896455 Tomkins et al., 2002 - Peripheral blood chromosome analysis in a 3.5 year old female with short stature, DD, and facial dysmorphism revealed 28% of cells with 45,X karyotype, and 72% with 46,X,r(X). XIST was present on the ring, but no XIST expression was detected. The ring was paternally derived and was not inactivated. The ring carried C(-43)A variant in the XIST promoter. The patient?s maternal grandmother also carried this variant on one of her X chromosomes, and it was more strongly associated with the active X, although she only showed 60:40 skewing of XCI. Since skewing increases with age, this result is not significantly different from the general population.
28947658 de Hoon et al., 2017 - 26 year old women with no ID or facial dysmorphism presented with ovarian dysgenesis aka premature ovarian insufficiency (POI). Normal karyotype, but SNP array analysis identified a 1.28 Mb deletion of the X-inactivation center (XIC) including XIST and several other genes. Several regions of LOH were also observed, consistent with history of parental consanguinity. X-inactivation was skewed 93:7 towards inactivation of the normal X.

Haploinsufficiency phenotype comments:

X-inactivation is typically random in females if an X-inactivation center is intact on each X chromosome. However, preferential skewed inactivation can occur due to cell survival and developmental pressures if a disease-associated mutation is present on one copy or if there is a structural anomaly such as a ring or translocation. The XIST gene is a crucial element for the ability of an X chromosome to inactivate, and without XIST inactivation can not occur. It is not, however, the only factor involved in X-inactivation patterns. See Yang et al, 2011, PMID:21553122 for review of background and mechanism. Since X-inactivation does not occur in XY males, a deletion of XIST would not be expected to result in an abnormal phenotype. In females, if a deletion or loss of function mutation occurred in XIST on a chromosome that carries a disease-causing mutation or was structurally abnormal, preferential inactivation of that chromosome would not be possible and an abnormal phenotype could be present. The phenotype associated would be contigent on the gene mutated or the structural anomaly present. Similarly, carriers of balanced X;autosome translocations that are not able to inactivate the normal X chromosome may have abnormal phenotypes. See PMID:15806320, 21067479, 20720308, 8728700 for examples. However, a deletion of XIST in the absence of an X-linked mutation or structural anomaly may not result in an abnormal phenotype. A haploinsufficiency score of 3 was assigned since loss of XIST does affect normal X-inactivation patterns in a female and would warrant an investigation for other disease-related mutations on the X chromosome. Additional functional evidence: Pugacheva et al., 2005 (PMID:15731119) perform functional studies using EMSA and other assays to demonstrate that transcription factor CTCF mediates XIST expression, and CTCF binding is impacted by two reported C(-43) variants in the XIST minimal promoter. C(-43)A variant abrogates CTCF binding to the XIST promoter while the C(-43)G variant substantially increases CTCF binding. Multiple functional studies in mice show that targeted mutagenesis of the mouse Xist promoter to increase Xist expression result in skewing of X-inactivation towards the targeted allele (Newall et al., 2001 PMID: 11230177, Nesterova et al., 2003 PMID: 12952890).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Focal duplications of XIST have not been reported. Muscatelli et al (PMID:1301147) report a male with a large duplication of Xq that results in two X-inactivation centers in tandem. They show that this duplication does not result in XIST transcription or late-replication of one of the regions, and expression levels of two X-linked genes in the region that do not escape inactivation were twice the levels of controls, consistent with a duplication. They conclude that a tandem duplication of the X-inactivation center, including XIST, does not result in abnormal inactivation of the chromosome. Nur et al 2016 (PMID:26639996) - Authors report a duplication at band Xq13.2 that includes XIST in a 15 year old female with typical (short stature, pulmonic stenosis, widely-spaced nipples) and atypical (Madelung deformity, menorrhagia) manifestations of Turner syndrome, as well as connective tissue laxity and von Willebrand disease. The abstract indicates this is the ?first case of selective X-inactive-specific-transcript locus duplication?, however unable to confirm this without more detail from the publication (full text unavailable).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.