Background SHOX mutations have previously been described as causes of Léri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), and idiopathic short stature. The loss of X chromosome—Turner syndrome or mosaic 45,X/46,XX or 46,XY—also leads to the heterozygous loss of SHOX in patients with short stature only or with features similar to LWD. The aim of this study was to assess the efficacy of the targeted screening for SHOX variants, which involved different methods in the laboratory analysis of short stature. We determined the significance and positive predictive value of short stature for the detection of SHOX variants. Methods Targeted screening for variants in SHOX involving MLPA, sequencing, karyotyping and FISH was performed in the short stature cohort (N = 174) and control cohort (N = 91). The significance of short stature and particular characteristics for the detection of SHOX variants was determined by Fisher’s exact test, and the probability of SHOX mutation occurrence was calculated using a forward/stepwise logistic regression model. Results In total, 27 and 15 variants influencing SHOX were detected in the short stature and control cohorts, respectively (p > 0.01). Sex chromosome aberrations and pathogenic CNV resulting in diagnosis were detected in eight (4.6%) and five (2.9%) patients of the short stature group and three (3.3%) and one (1.1%) individuals of the control group. VUS variants were discovered in 14 (8.0%) and 11 (12.1%) individuals of the short stature and control groups, respectively. MLPA demonstrated the detection rate of 13.22%, and it can be used as a frontline method for detection of aberrations involving SHOX. However, only mosaicism of monosomy X with a higher frequency of monosomic cells could be reliably discovered by this method. Karyotyping and FISH can compensate for this limitation; their detection rates in short stature group were 3.55% and 13.46% (N = 52), respectively. FISH proved to be more effective than karyotyping in the study as it could reveal cryptic mosaics in some cases where karyotyping initially failed to detect such a clone. We suggest adding FISH on different tissue than peripheral blood to verify sex-chromosome constitution, especially in cases with karyotypes: 45,X; mosaic 45,X/46,XX or 46,XY; 46,Xidic(Y) detected from blood; in children, where mosaic 45,X was detected prenatally but was not confirmed from peripheral blood. The correlation of short stature with the occurrence of SHOX mutations was insignificant and short stature demonstrates a low positive predictive value-15.5% as unique indicator for SHOX mutations. The typical skeletal signs of LWD, including Madelung deformity and disproportionate growth, positively correlate with the findings of pathogenic SHOX variants (p < 0.01) by Fisher’s exact test but not with the findings of VUS variants in SHOX which are more prevalent in the individuals with idiopathic short stature or in the individuals with normal height.

中文翻译：

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身材矮小和 SHOX（身材矮小同源框）变体——使用各种策略进行筛选的效果

背景 SHOX 突变以前曾被描述为 Léri-Weill 软骨发育不良 (LWD)、Langer 中间体发育不良 (LMD) 和特发性身材矮小的原因。X 染色体的缺失——特纳综合征或镶嵌 45,X/46,XX 或 46,XY——也导致仅身材矮小或具有与 LWD 相似特征的患者的 SHOX 杂合缺失。本研究的目的是评估针对 SHOX 变体的靶向筛查的有效性，这涉及到身材矮小的实验室分析中的不同方法。我们确定了身材矮小对检测 SHOX 变异的意义和阳性预测值。方法 在身材矮小队列 (N = 174) 和对照组 (N = 91) 中进行 SHOX 变异的靶向筛查，包括 MLPA、测序、核型分析和 FISH。通过Fisher精确检验确定SHOX变异检测的身材矮小和特定特征的重要性，并使用前向/逐步逻辑回归模型计算SHOX突变发生的概率。结果 在身材矮小和对照组中，分别检测到 27 个和 15 个影响 SHOX 的变异（p > 0.01）。在身材矮小组的 8 名 (4.6%) 和 5 名 (2.9%) 患者以及对照组的 3 名 (3.3%) 和 1 名 (1.1%) 患者中检测到导致诊断的性染色体畸变和致病性 CNV。VUS 变异分别在身材矮小和对照组的 14 名 (8.0%) 和 11 名 (12.1%) 个体中发现。MLPA 的检出率为 13.22%，它可以用作检测涉及 SHOX 的像差的一线方法。然而，这种方法只能可靠地发现具有更高频率单体细胞的单体 X 嵌合体。核型分析和 FISH 可以弥补这一限制；身材矮小组的检出率分别为3.55%和13.46%（N=52）。在该研究中，FISH 被证明比核型分析更有效，因为它可以在核型分析最初未能检测到这种克隆的某些情况下揭示神秘的镶嵌。我们建议在与外周血不同的组织上添加 FISH 以验证性染色体构成，特别是在核型为：45，X 的情况下；马赛克 45,X/46,XX 或 46,XY; 46，从血液中检测到的 Xidic(Y)；在儿童中，马赛克 45,X 在产前被检测到，但未从外周血中得到证实。身材矮小与 SHOX 突变发生的相关性不显着，身材矮小表现出较低的阳性预测值 - 15.5% 作为 SHOX 突变的唯一指标。LWD 的典型骨骼体征，包括 Madelung 畸形和不成比例生长，与 Fisher 精确检验发现的致病性 SHOX 变异 (p < 0.01) 呈正相关，但与 SHOX 中 VUS 变异的发现无关，后者在患有以下疾病的个体中更为普遍特发性身材矮小或身高正常的个体。