ClinGen Dosage Sensitivity Curation Page

SHOX

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11403039 Huber et al. (2001) analyzed SHOX in 8 families (22 patients) with dyschondrosteosis and found 3 deletions and 5 point mutations (including 4 nonsense changes).
12402330 Niesler et al. (2002) describe an online database (www.shox.uni-hd.de) that contains 29 mutations in SHOX from individuals with short stature phenotypes. The most common nonsense mutation reported is R195X, seen in 7 patients. This database does not include SHOX deletions.
11889216 Rappold et al. (2002) analyzed SHOX in 900 patients with short stature. They found 9 intragenic mutations and 3 whole gene deletions.

Haploinsufficiency phenotype comments:

Haploinsufficiency of SHOX results in short stature phenotypes ranging from severe (Leri-Weill dyschondrosteosis) to mild short stature. Males and females are both affected, though females often have a more severe phenotype. Homozygous deletions of SHOX causes Langer mesomelic dysplasia (OMIM 249700). There have been multiple reports describing deletions of enhancer elements of SHOX in patients with LWD or ISS. Two recent reports describe a novel, recurrent downstream enhancer (PMID 22791839) and the first reported deletion of an upstream enhancer of SHOX (PMID 22071895) in a patient with ISS.

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:

There is currently insufficient evidence in support of clinical phenotypes associated with increased SHOX gene dosage (duplication). Although reports of whole gene duplication in association with clinical findings exist in the literature (summarized below), due to variability in breakpoints across reported cases and controls (focal, nonfocal, complete and partial gene involvement), inconsistent phenotypic findings in cases (which may in part be due to a bias of ascertainment), and variability in phenotypic expression, the triplosensitivity score for SHOX is 0. Relevant literature regarding whole gene and partial gene duplication of SHOX is further summarized below. Thomas et al. (2009; PMID 19533800) mapped four cases of SHOX duplications. All duplications included only the SHOX gene, but the duplications were different sizes. The families were referred for various phenotypes, but based on inheritance/segregation patterns, the authors concluded that the SHOX duplications were likely only associated with height and not the other phenotypes. The authors remarked that: "effect of the duplications on stature was variable: height appeared to be elevated in some carriers, particularly in those with the largest duplications, but was still within the normal range." Since SHOX is known to have long-range transcriptional enhancers, the authors hypothesize that the flanking enhancer regions included in the SHOX duplications may affect height and lead to the variability in height of the patients with SHOX duplications. The authors conclude that more cases should be analyzed before the pathogenicity of SHOX dups can be determined. Roos et al. (2009; PMID 19938087) reported a paternally inherited SHOX duplication in a female with ID, congenital abnormalities, and normal growth. The father also had normal growth. The duplication included all the enhancer regions of SHOX, so the authors concluded that duplication of SHOX does not result in increased height, but it could be a risk factor. Benito-Sanz et al. (2011; PMID 21147883) analyzed 122 patients with LWD and 613 patients with ISS and found 4 probands with complete duplications of SHOX. They did not find any duplications in 340 individuals with normal height or 104 individuals with overgrowth. Of the 4 female patients with complete SHOX duplications, 1 was referred for LWD and had normal height and 3 were referred for ISS. The authors explain the SHOX duplication and association with short stature by these possibilities (from manuscript): "1) the extra whole or partial copy/copies disrupt the normal copy of SHOX and the inserted copy/copies is/are not functional because they lack the necessary regulatory sequences; 2) the extra copy/copies is/are present in tandem with the normal copy, either affecting SHOX regulatory sequences or modifying the distance between the gene and the enhancers or regulatory sequences; and 3) the extra copy/copies is/are localized further upstream or downstream from the normal copy, which would increase the distance between the normal copy and the regulatory regions." The complex regulatory structure of the SHOX locus has been hypothesized to contribute to incomplete association of gene duplication with tall stature. Tropeano et al. (2016, PMID: 27073233) identified SHOX microduplication in 2 of 90 adults from a series of adult patients with autism spectrum disorders (ASD). They subsequently performed a case-control meta-analysis and identified SHOX whole gene or partial gene duplication in 89 (91 total) of 26,574 patients referred for clinical genomic microarray analysis (including 18,857 with neurodevelopmental disorders (NDD) and 3,541 with ASD) compared to 25 of 12,594 population-based controls. In total 62 cases and 21 controls encompassed at least one isoform of SHOX (defined as "whole gene duplication") and 29 cases versus 4 controls were partial overlapping duplications. Secondary genomic alterations were observed in 15 of 91 (16.5%) of cases, 7 of which were classified as pathogenic or likely pathogenic. A statistically significant enrichment of duplications in this region was observed for both NDD and ASD populations (all duplication types combined). The authors propose that copy number gain of either the SHOX gene itself and/or flanking enhancer elements represents a pathogenic variant with reduced penetrance and variable expressivity, with median penetrance values of 3.6% (95% CI 2.1% to 6.1%) for ASD and 8.6% (95% CI 5.8% to 13.3%) for NDD. For additional cases involving duplications of downstream enhancer regions in individuals with Leri-Weill and idiopathic short stature phenotypes, see PMID: 22020182. Partial gene duplications of SHOX: PMID: 20847698: Gervasini et al. (2010) describe partial SHOX duplications in 5 patients with Mayer-Rokitansky-Kuster-Hauser syndrome. The authors note in their conclusions: "In this cohort, none of the five patients with MRKH syndrome with a SHOX gene duplication showed skeletal abnormalities, which are expected in individuals with SHOX gene haploinsufficiency, and height values were within the expected parental targets. Although the consequences of partial SHOX duplications at the protein level are unknown, it is likely that they result in the production of aberrant proteins. It may be hypothesized that a gain of function, interfering at a specific time point with early embryonic development, could be implicated in the development of MRKH syndrome rather than a loss of function resulting in absence of the gene product. This point should be investigated by targeted studies."

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.