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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.

Short stature and SHOX (Short stature homeobox) variants—efficacy of screening using various strategies