SHOX is located in the pseudoautosomal region 1 (PAR1) on the short arm of the X and Y chromosomes. Located upstream and downstream of SHOX are highly conserved non-coding elements (CNEs), some of which have been shown to be important SHOX enhancer sequences. Mutations in SHOX or its regulatory regions cause a range of disorders associated with short stature, including LWD, LMD, and ISS, as SHOX is a known transcription factor highly expressed in tissues responsible for bone development (Benito-Sanz et al. 2012b).
LWD is a dominant skeletal disorder characterised by short stature, mesomelic shortening of the limbs, and the characteristic Madelung deformity. LMD is a more severe form of LWD and is a result of mutations in both SHOX alleles (while LWD is associated with pathogenic variants in one SHOX allele) (Bertorelli et al. 2007, Campos-Barros et al. 2007, Shears et al. 2002, Zinn et al. 2002). ISS classifies individuals with a height below the third centile in whom no identifiable disorder is present. Heterozygous mutations of SHOX and/or its regulatory elements are detected in approximately 60% of LWD patients and approximately 5-15% of ISS cases. Homozygous or compound heterozygous mutations of SHOX and/or its enhancers are detected in 75% of LMD patients (Benito-Sanz et al. 2006, Benito-Sanz et al. 2012a, Chen et al. 2009, Huber et al. 2006).
In the remaining cases, the cause for short stature remains unknown. In individuals with a SHOX-related disorder, 70-80% of mutations are due to a complete gene deletion, 2-6% are from a partial deletion, and 20-25% are from point mutations, including small deletions or insertions (Binder 2011, Caliebe et al. 2012).
An extra copy of the SHOX gene and the entire SHOX regulatory region is present in individuals with tall stature and an additional X or Y chromosome, where all three copies of SHOX are fully expressed. When a duplication does not include all flanking regulatory elements, the effect on SHOX expression is difficult to predict. Duplications of SHOX alone or including various lengths of the SHOX regulatory elements have been reported in LWD and ISS patients, and in SHOX-specific cohorts, the frequency of these duplications has been estimated at 0.33% (Bunyan et al. 2023). Reported duplications include those extending upstream or downstream of the SHOX area (Bunyan et al. 2016, Bunyan et al. 2021, Bunyan et al. 2023), as well as those exclusively affecting downstream PAR1 regions (Eid et al. 2020, Hirschfeldova et al. 2012, Hirschfeldova and Solc 2017). In terms of the clinical significance of these types of duplications, since the occurrence is low, there has been limited evidence supporting the association between such CNVs and short stature. However, one study showed that there was a statistically significant increase in the frequency of these duplications in individuals with LWS or ISS compared to unaffected individuals (Hirschfeldova and Solc 2017).
The P018 SHOX probemix can detect most deletions and duplications and therefore complements sequence analysis of SHOX.
More information is available on http://www.ncbi.nlm.nih.gov/books/NBK1215/.
