SHOX Whole Gene Duplications Are Overrepresented in SHOX Haploinsufficiency Phenotype Cohorts

Abstract

Transcription of SHOX is dependent upon the interaction of the gene with a complex array of flanking regulatory elements. Duplications that contain flanking regulatory elements but not the SHOX gene have been reported in individuals with SHOX haploinsufficiency syndromes, suggesting that alterations to the physical organisation or genomic architecture may affect SHOX transcription. Individuals with tall stature and an additional X or Y chromosome have an extra copy of both the SHOX gene and the entire SHOX regulatory region, so all three copies of SHOX can be expressed fully. However, for a duplication of the SHOX gene that does not include all of the flanking regulatory elements, the potential effect on SHOX expression is difficult to predict. We present nine unpublished individuals with a SHOX whole gene duplication in whom the duplication contains variable amounts of the SHOX regulatory region, and we review 29 similar cases from the literature where phenotypic data were clearly stated. While tall stature was present in a proportion of these cases, we present evidence that SHOX whole gene duplications can also result in a phenotype more typically associated with SHOX haploinsufficiency and are significantly over-represented in Leri-Weill Dyschondrosteosis and idiopathic short stature probands compared to population controls. Although similar-looking duplications do not always produce a consistent phenotype, there may be potential genotype-phenotype correlations regarding the duplication size, regulatory element content and the breakpoint proximity to the SHOX gene. Although ClinGen (clinicalgenome.org) do not currently consider SHOX whole gene duplications to be clinically significant, the ClinGen triplosensitivity score does not take into account the context of the duplication, and more is now known about SHOX duplications and the role of flanking elements in SHOX regulation. The evidence presented here suggest that these duplications should not be discounted without considering the extent of the duplication and the patient phenotype, and should be included on diagnostic laboratory reports as variants of uncertain significance. Given the uncertain pathogenicity of these duplications, any reports should encourage the exclusion of all other causes of short stature where possible.

Klinefelter Syndrome: A Genetic Disorder Leading to Neuroendocrine Modifications and Psychopathological Vulnerabilities in Children—A Literature Review and Case Report

“…Conversely, the augmented body height could plausibly be attributed to an overexpression of growth-associated genes, such as short stature homeobox (SHOX), given that individuals with 47,XXY karyotypes harbor three copies of this gene [91]. An extra copy of the SHOX gene and all associated regulatory elements would be expected to determine overexpression; nevertheless, duplications of the entire SHOX gene but only part of the regulatory region have no certain genotype-phenotype correlations, exhibiting a wide range of possible phenotypes [92]. Moreover, Tropeano et al (2016) demonstrated that SHOX microduplications represent a low penetrance risk factor for autism spectrum disorders and related neurodevelopmental conditions in males and females [93].…”