Screening of<i>SHOX</i>gene sequence variants in Saudi Arabian children with idiopathic short stature

Alharthi, Abdulla A.; El-Hallous, Ehab I.; Talaat, Iman M.; Alghamdi, Hamed A.; Almalki, Matar I.; Gaber, Ahmed

doi:10.3345/kjp.2017.60.10.327

Cited by 8 publications

(3 citation statements)

References 34 publications

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“…In patients with ISS, the prevalence of SHOX mutations varies from 2-15% depending on other clinical features and the technologies used (Benito-Sanz et al, 2006;Benito-Sanz et al, 2012;Chen et al, 2009;Huber et al, 2006). However, the number of detected variants including intronic mutations influence the splicing of SHOX either with unambiguous or unclear significance for linear growth of individuals in the group of children with short stature is still growing (Thomas et al, 2009;Alharthi et al, 2017;Sandoval et al, 2014;Durand et al, 2011). Chromosomal abnormalities in the sex chromosomes that lead to the heterozygous deletion of SHOX are a cause of short stature in patients with TS or patients with ISS (Oliveira & Alves, 2011).…”

Section: Introduction Backgroundmentioning

confidence: 99%

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

Capkova

Rosenberger

et al. 2020

PeerJ

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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.

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Section: Introduction Backgroundmentioning

confidence: 99%

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

Capkova

Rosenberger

et al. 2020

PeerJ

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“…In contrast, Bakır et al ( 21 ) found no variation in the SHOX gene in 37 patients. Alharthi et al ( 22 ) found only one variation in exon 4 of SHOX while rest of patients had polymorphisms in exons 1, 2, 4, and 6. Gürsoy et al ( 23 ) found three point variations and one whole gene deletion in 15 patients from four different families.…”

Section: Discussionmentioning

confidence: 99%

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Srivastava,

Tyagi,

Bamba

et al. 2023

Jcrpe

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Objective: Short stature homeobox ( SHOX ) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.

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“…Next-generation sequencing has also shown that many genetic disorders that were previously thought to be only associated with skeletal dysplasia can present as dominant forms of apparent idiopathic short stature. These include, for example, abnormalities in the gene for the retinoic acid degrading enzyme CYP26C1 (15), coding and non-coding regions of the short-stature homeobox-containing gene SHOX (16,17), the ACAN gene coding for the growth plate extracellular matrix proteoglycan aggrecan (18,19), the natriuretic peptide receptor-B gene NPR2 (20,21,22) and the gene encoding Indian Hedgehog ( IHH ) (23).…”

Section: The Genetic Basis Of Short Staturementioning

confidence: 99%

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

Wit

Deeb

Bin-Abbas

et al. 2019

Jcrpe

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It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

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Screening ofSHOXgene sequence variants in Saudi Arabian children with idiopathic short stature

Cited by 8 publications

References 34 publications

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

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

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

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