Xp22.31 recurrent region (includes STS)

  • 3
    Haplo
    Score
  • 40
    Triplo
    Score

Region Facts

Region Name
Xp22.31 recurrent region (includes STS)
Cytoband
Xp22.31
Genomic Coordinates
GRCh37/hg19 chrX:6455812-8124954 NCBI Ensembl UCSC
GRCh38/hg38 chrX:6537771-8156913 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37417
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
This review refers to the Xp22.31 recurrent region (includes STS). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Dosage Sensitivity Unlikely (40)
Related Links:
Last Evaluated:
07/01/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence 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).
NOTE:

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 (TS) Score Details

TS Score:
40
TS Evidence Strength:
Dosage Sensitivity Unlikely (Disclaimer)
TS Evidence Comments:
Duplication of the Xp22.31 (STS) region has evidence refuting its significance. Duplications of this region are common in the general population (~0.32-0.41%) and have consistently been found to not be enriched within the clinical population (PMID: 21355048, 32766777). Recent studies of duplication carriers identified through large cohort studies on the general population have also shown that carrier individuals perform similarly to non-carrier controls on neurocognitive tests. Therefore, the triplosensitivity score for this region is Dosage Sensitivity Unlikely. Additional relevant literature is summarized below: PMID 32766777 Gubb et al. (2020) analyzed the effect of the Xp22.31 (STS) duplication on cognitive performance, phenotypic features, and general measures of functioning of 414 male and 938 female duplication carrier adults recruited from the UK Biobank cohort (a large, genotyped population) compared to non-carrier controls from the same population. Significant differences were observed for 0 of 7 total measurements of cognitive function in Male carriers compared to controls and in 1 of 7 measurements of cognitive function (symbol digit substitution task) in female carriers. The difference in symbol digit substitution task performance in females did not remain significant after correcting for multiple testing (Benjamini-Hochberg corrected p-value). Carrier individuals (male and female) did not differ from controls in their highest level of academic qualifications. The clinical diagnosis rates of developmental and mood/anxiety disorders (ex: depression and dyslexia) did not differ between carrier individuals and controls. Minor differences in the rates of hernias, gastroesophageal reflux disease without oesophagitis, and volumes of brain regions (left putamen and ventricle) were observed in male or female duplication carriers. However, in all instances the differences did not remain significant after correcting for multiple testing. PMID 32016944 Massimino et al. (2020) report a single patient with the recurrent Xp22.31 duplication. The clinical findings in the reported patient include intellectual disability, language delay, hyperopic astigmatisms, and Poland sequence. Parental testing demonstrated that the duplication was de novo. PMID 31486937 MacColl et al. (2019) report a single patient with a duplication involving the Xp22.31 region. The clinical findings in this patient include club feet, microcephaly, hypotonia, failure to thrive, seizures, and an abnormal MRI. The duplication was inherited from a mother who was healthy except for mild club feet. PMID 30603611 Brinciotti et al. (2019) report 2 patients with the recurrent Xp22.31 duplication. The clinical findings in the reported patients include seizures and learning difficulties. Parental testing demonstrated that the duplication was maternally inherited from a mother who was reportedly normal with no seizure history. PMID 29789371 Addis et al. (2018) reported four patients with the recurrent Xp22.31 duplication in their cohort of patients with Rolandic epilepsy. Parental testing was reported for two of these patients, with one duplication representing a de novo event and the second representing a paternally inherited event from a father with a history of dyslexia. PMID 30733660 Pavone et al. (2018) report a single patient with the recurrent Xp22.31 duplication. The reported clinical findings include developmental delay, intellectual disability, microcephaly, and dysmorphic craniofacial findings. The duplication was not maternally inherited. A paternal sample was not available for testing. PMID: 24800990 Esplin et al. (2014) report a series of nine patients from five families (five males and four females) with duplications involving the recurrent Xp22.31 region. Two of the nine patients had the recurrent ~1.6 Mb duplication including STS. Two patients had a partial duplication of STS, and the other five subjects' duplications did not overlap the STS gene. The reported clinical findings in the patients with the recurrent duplication include cognitive dysfunction, motor delay, seizures, and feeding difficulties. These findings were also observed in the seven individuals with partial duplications of the recurrent Xp22.31 region. Parental testing demonstrated that all the duplications were maternally inherited, with both patients with the recurrent ~1.6 Mb duplication inheriting it from an apparently unaffected mother. PMID 21739574 Furrow et al. (2011) report 72 males submitted to their laboratory for clinical microarray testing with a duplication involving the Xp22.31 (STS) region. The overall frequency of these duplications within their clinical cohort was 0.2% (72/35,441 cases). The phenotypic features reported in these patients included developmental delay, cardiac anomalies, ambiguous genitalia, polydactyly, and dysmorphic features. Secondary genetic findings of clinical significance were observed in ~14% (10/72) of cases. Parental testing was performed for 40 patients, and in each case, it was found to be inherited from an apparently normal mother, with multiple families showing additional unaffected carrier individuals (sibling, uncle, etc..). 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". PMID 20132918 Li et al. (2011) report a series of 29 Xp22.31 duplications of varying size from a total of 7793 patients referred for clinical microarray testing. The reported duplications were of variable size, with the smallest only involving the STS, and most encompassing HDHD1A, STS, VCX, PNPLA4, and VCX2. Duplications were observed in 29/7793 (0.37%) patients and 3/2026 (0.15%) controls, demonstrating a lack of enrichment within the clinical population (p=0.1295). The reported clinical presentation in their Xp22.31 duplication carriers included intellectual/learning disability, behavioral abnormalities, and failure to thrive. X-inactivation studies from 16 female carriers demonstrated that 2/7 affected female carriers had skewed inactivation of the normal X, 4/8 normal female carriers had skewed inactivation of the duplicated X, and 8/16 female carriers (4 normal and 4 affected) had random X-inactivation. The majority of these duplications represent inherited events, with the duplication being inherited from both affected and apparently unaffected parents. PMID 21355048 Liu et al. (2011) report 58 recurrent Xp22.31 duplications and 3 triplications from a large cohort referred for clinical microarray testing. The overall frequency of this duplication within their cohort was 0.289% (58/20,095 cases), with the male and female prevalence being 0.226% and 0.289%, respectively. Analysis of a control cohort identified the duplication in 0.41% (20/5088) of individuals, with the male and female prevalence being 0.182% and 0.523%, respectively. Neither of these was different from the case frequency (p = 1 for male, p = 0.28 for female). Clinical information was available for 14 of the recurrent duplication carriers with most patients showing developmental delays (motor and/or speech) and behavioral or social interaction issues consistent with autism. Of the two males and one female with a triplication, all had developmental delay, and the two males had aggressive behavior issues. Parental testing was performed for 17 subjects, and in all instances the duplication was inherited. PMID 22140086 Faletra et al. (2011) describe an Italian male with a de novo ~1.5Mb duplication of the Xp22.31 (STS) recurrent region. The individual was described as having hypotonia, developmental delay, and minor dysmorphic features. The duplication was not identified in 2,055 Italian controls.
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) ()