ClinGen Dosage Sensitivity Curation Page

Xp22.31 recurrent region (includes STS)

  • Curation Status: Complete
  • id: ISCA-37417
  • Date last evaluated: 2016-04-07
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: Triplosensitivity unlikely


Location Information

Select assembly: (NC_000023.10) ()

Haploinsufficiency phenotype comments:

Deletion of this region is associated with X-linked ichthyosis (XLI). Please see OMIM entry 308100 for further discussion. See also the linked issue for the STS gene outlining the evidence supporting haploinsufficiency of STS in XLI. Individuals with deletions of this region may be at increased risk for attention deficit hyperactivity disorder (PMID: 18413370).

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: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely

Triplosensitivity phenotype comment:

Although reports of Xp22.31 (STS) region duplication in association with clinical findings exist in the literature (summarized below), due to inconsistency in the phenotypic findings across cases (which may in part be due to a bias of ascertainment), variability in phenotypic expression, and lack of enrichment of duplications in the clinical population, the triplosensitivity score for this region is dosage sensitivity unlikely. Furrow et al. (PMID: 21739574) contend that these duplications are benign, citing the following evidence: 72 males submitted to their laboratory for clinical microarray testing (total n = 35,441) found to have a duplication of STS, 56% were found to have inherited the duplication from a phenotypically normal mother, including one case in which a phenotypically normal uncle had the same duplication as his affected nephews. In 14% of these 72 cases, the probands were found to have an additional CNV that was believed to be causative of their symptoms. They also identified the duplications in three females referred for testing who had inherited them from phenotypically normal fathers. This paper cites other studies in which STS duplications in males and females are found to be inherited from reportedly normal mothers and fathers, as well as instances of STS duplications within databases of genomic variation in control populations. The authors do note that, "contributions to a digenic two-hit model or reduced-penetrance dosage effects of other genes in the genomic region encompassed by the CNV gain cannot be ruled out by the present data". Li et al. (PMID:20132918) question whether the duplication could be a risk factor for intellectual disability. They report a series of 29 Xp22.31 duplications of varying size from a total of 7793 patients referred for clinical microarray testing, in addition to some cases previously reported in the literature, for a total of 41 cases. The duplicated region in the combined sample ranged from 149 kb to 1.9 Mb and involved the STS gene in all probands. The smallest duplication (149 kb) was located from 7.18 Mb to 7.32 Mb involving only the STS gene. The largest duplicated region contained six OMIM genes, including VCX3A, HDHD1A, STS, VCX, PNPLA4, and VCX2. In most probands (33/40) the duplication involved HDHD1A, STS, VCX and PNPLA4. The authors point out that this duplication is seen more often in patients than controls (0.37% vs. 0.15%, respectively), but relative prevalence did not reach statistical significance. They note that this duplication does not appear to be associated with a clear, distinct phenotype, but also acknowledge the possibility of reduced penetrance/expressivity as is observed for a number of other genomic regions, such as 3q29, 7q11.23, and 22q11.2. They conclude that there was "enough evidence to consider this duplication as a risk factor or modifier for ID and behavior problems," but acknowledge that they "cannot completely exclude the possibility that this duplication is a rare population variant." Liu et al. (PMID: 21355048) discuss the presence of Xp22.31 duplications and triplications amongst a large cohort referred for clinical microarray testing (n=20,095). They report observing the duplication amongst 0.289% of cases, but amongst 0.41% of controls (n=5088), a difference that did not reach statistical significance. Triplication of Xp22.31 was found in three cases but not in controls. The authors note that 64% of case individuals with a duplication (males and females) were reported to have developmental delays. Further, 64% of males in whom clinical information was able to be obtained were reported to have behavioral or social interaction issues. Of the two males and one female with a triplication, all had developmental delay, and the two males had aggressive behavior issues. The authors propose that the triplication of the Xp22.31 region may be more penetrant in regards to abnormal phenotype than the duplication. PMID22140086: Faletra et al. describe an Italian male with a de novo ~1.5Mb duplication of Xp22.31 (chrX: 6526735-8101017) (GRCh36/hg18). The individual was described as having hypotonia, developmental delay, and minor dysmorphic features. The duplication was not identified in 2,055 Italian controls. Esplin et al (2014, PMID: 24800990) report a series of nine individuals from 5 families--5 males and 4 females--with maternally inherited duplications of Xp22.31. Two of the nine subjects had ~1.5 Mb duplication including STS. Subjects 7 and 8 had a partial duplication of STS, and the other subjects' duplications did not overlap the STS gene. Although the authors describe an abnormal phenotype for these individuals that includes talipes abnormalities and intellectual disability, the possibility of ascertainment bias of this cohort cannot be ruled out. One of the affected mothers was demonstrated to have skewed X-inactivation, but no other individual was tested for X-inactivation. There was no testing performed for maternally-related unaffected males who may be carriers of the duplication. The authors also note that three of the probands were siblings of a consanguineous union, in which the mother was affected. The authors do acknowledge the increased risk of intellectual disability due to a recessive etiology in this family. The studies of these individuals was performed on oligo arrays, which do not demonstrate the genotyping capabilities of SNP arrays. Therefore, whether the mother was also a child of a consanguineous union is not addressed by the testing performed or mentioned from the family history.

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.