ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-19327
• Date last evaluated: 2018-09-13
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/412
• OMIM: https://omim.org/entry/300747

Location Information

• Xp22.31
• GRCh37/hg19 chrX: 7,065,293-7,272,684
• See linked regions:
• Xp22.31 recurrent region (includes STS)

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: ICHTHYOSIS, X-LINKED; XLI

Evidence for loss of function phenotype

PubMed ID	Description
2813406	Shapiro et al. (1989) describe an individual with X-linked ichthyosis (XLI) and a 40 kb deletion involving exons 2-5 of STS.
10692123	Valdes-Flores et al. (2000) describe an XLI patient with a deletion of exons 2-10 in STS.
9252398	Alperin and Shapiro (1997) discuss six point mutations identified in STS, including one frameshift resulting in premature truncation. In vitro functional expression studies showed that all 6 mutants lacked STS enzymatic activity.

• Loss of function phenotype comments: Loss of function mutations in STS are most commonly associated with X-linked ichthyosis, or steroid sulfatase deficiency, a condition most often seen in males. It is estimated that ~85% of STS deficiency is caused by whole STS gene deletions (OMIM #300747). Affected females have been reported; these individuals were presumed (though not proven) to be homozygous (Csorsz 1928, see OMIM #308100). Mild abnormalities have been reported in heterozygous females, including corneal opacities (PMID: 5303230) and mild skin findings (PMID: 5307231). Individuals with deletions including genes other than STS may show features of a contiguous gene syndrome. Phenotype would vary according to which additional genes were deleted. Recent evidence has suggested that individuals with X-linked ichthyosis may be at increased risk for attention deficit hyperactivity disorder, communication deficits, and/or autism (PMID: 18413370). See this article and subsequent articles for additional information. Of note, individuals identified with an autism phenotype had larger deletions that included the NLGN4 gene. For a review of evidence relating to dosage sensitivity of the recurrent Xp22.31 region that includes STS, please see the linked region in this review.

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.

Evidence for Triplosenstive Phenotype

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

• Triplosensitivity phenotype comment: The evidence presented within this entry concerns focal duplications, involving the STS gene alone. Li et al. (PMID: 20132918) report one case of a female with a duplication encompassing only the STS gene amongst a larger case set of 29 individuals with Xp22.31 duplications. The phenotype of this particular case (case 29) is not individually defined; rather, the phenotype of the entire cohort is reported in aggregate. Therefore, since we do not have phenotypic information about this case, we did not count this case as evidence. The authors also report an instance of an STS gene duplication within their control dataset. For a review of evidence relating to dosage sensitivity of the recurrent Xp22.31 region that includes STS, please see the linked region in this review.

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.