Abstract
BackgroundSHOX 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.MethodsTargeted 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.ResultsIn 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.
Highlights
BackgroundGrowth retardation, a common condition leading to reduced height, is defined as the deviation of an individual’s height of more than two standard deviation score (SDS) below the mean in the population or the estimated familial target height (Amin, Mushtaq & Alvi, 2015)
SHOX gene mutations have previously been described as causes of Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), idiopathic short stature (ISS), and its haploinsufficiency is described as the cause of growth restriction in Turner syndrome (TS) (Belin et al, 1998; Rao et al, 1997; Benito-Sanz et al, 2005; Benito-Sanz et al, 2006; Benito-Sanz et al, 2011; Hirschfeldova et al, 2012; Zinn et al, 2002; Campos-Barros et al, 2007; Rappold et al, 2002)
We could discover the presence of chromosomally different cell clones—45,X or 47,XXX—which were not detected by karyotyping in 4 cases overall in the short stature group using FISH on buccal smears—see cases below (Table S1)
Summary
BackgroundGrowth retardation, a common condition leading to reduced height, is defined as the deviation of an individual’s height of more than two standard deviation score (SDS) below the mean in the population or the estimated familial target height (Amin, Mushtaq & Alvi, 2015). SHOX gene mutations have previously been described as causes of Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), idiopathic short stature (ISS), and its haploinsufficiency is described as the cause of growth restriction in Turner syndrome (TS) (Belin et al, 1998; Rao et al, 1997; Benito-Sanz et al, 2005; Benito-Sanz et al, 2006; Benito-Sanz et al, 2011; Hirschfeldova et al, 2012; Zinn et al, 2002; Campos-Barros et al, 2007; Rappold et al, 2002). 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). 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.
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