Bunyan David J, Hobbs James I, Duncan-Flavell Philippa J, Howarth Rachel J, Beal Sarah, Baralle Diana, Thomas Nicholas Simon
Wessex Genomics Laboratory Service, Salisbury District Hospital, Salisbury, UK.
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Cytogenet Genome Res. 2022;162(11-12):587-598. doi: 10.1159/000530171. Epub 2023 Mar 16.
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 We present nine unpublished individuals with a SHOX whole gene duplication in whom the duplication contains variable amounts of the SHOX regulatory region, and we review 29 similar cases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 overrepresented 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 does 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 suggests that these duplications should not be discounted without considering the extent of the duplication and the patient phenotype, and should be included in 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.
SHOX基因的转录依赖于该基因与一系列复杂的侧翼调控元件之间的相互作用。在患有SHOX单倍剂量不足综合征的个体中，已报道存在包含侧翼调控元件但不含SHOX基因的重复，这表明物理组织或基因组结构的改变可能会影响SHOX的转录。身材高大且有额外一条X或Y染色体的个体，SHOX基因和整个SHOX调控区域都有一个额外的拷贝，因此SHOX的所有三个拷贝都能充分表达。然而，对于不包含所有侧翼调控元件的SHOX基因重复，其对SHOX表达的潜在影响难以预测。我们报告了9例未发表的携带SHOX全基因重复的个体，其重复包含不同数量的SHOX调控区域，并且我们回顾了文献中29例类似病例，其中明确陈述了表型数据。虽然这些病例中有一部分存在身材高大的情况，但我们提供的证据表明，SHOX全基因重复也可能导致一种更典型地与SHOX单倍剂量不足相关的表型，并且与人群对照相比，在Leri-Weill软骨发育不全和特发性矮小先证者中显著多见。尽管外观相似的重复并不总是产生一致的表型，但关于重复大小、调控元件含量以及断点与SHOX基因的接近程度，可能存在潜在的基因型-表型相关性。虽然临床基因组资源（ClinGen）目前不认为SHOX全基因重复具有临床意义，但ClinGen三倍体敏感性评分并未考虑重复的背景情况，并且现在我们对SHOX重复以及侧翼元件在SHOX调控中的作用有了更多了解。此处提供的证据表明，在不考虑重复范围和患者表型的情况下，不应忽视这些重复，并且应将其作为意义未明的变异纳入诊断实验室报告。鉴于这些重复的致病性不确定，任何报告都应鼓励尽可能排除所有其他矮小原因。
