scholarly journals Improved Molecular Diagnostics of Idiopathic Short Stature and Allied Disorders: Quantitative Polymerase Chain Reaction-Based Copy Number Profiling of SHOX and Pseudoautosomal Region 1

2010 ◽  
Vol 95 (6) ◽  
pp. 3010-3018 ◽  
Author(s):  
Barbara D'haene ◽  
Jan Hellemans ◽  
Margarita Craen ◽  
Jean De Schepper ◽  
Koen Devriendt ◽  
...  
Keyword(s):  
Short Stature ◽  
Molecular Diagnostics ◽  
Copy Number ◽  
Quantitative Polymerase Chain Reaction ◽  
Molecular Genetic ◽  
Significant Proportion ◽  
Idiopathic Short Stature ◽  
Pseudoautosomal Region ◽  
Shox Gene ◽  
Copy Number Changes

Abstract Context: Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding the SHOX gene account for a significant proportion of patients with idiopathic short stature (ISS) and allied disorders, such as Leri-Weill dyschondrosteosis. Objective: Several shortcomings of current strategies for copy number profiling of the SHOX region prompted us to develop an improved test for molecular diagnostics of the SHOX region. Design and Results: We introduced a quantitative PCR (qPCR)-based copy number profiling test, consisting of 11 amplicons targeting clinically relevant regions, i.e. the SHOX gene and regulatory regions. To ensure an optimal sensitivity and specificity, this test was validated in 32 controls and 18 probands with previously identified copy number changes. In addition, 152 probands with SHOX-associated phenotypes were screened, revealing 10 novel copy number changes. Conclusion: This highly validated qPCR test supersedes other approaches for copy number screening of the SHOX region in terms of reliability, accuracy, and cost efficiency. In addition, another strong point is the fact that it can be easily implemented in any standard equipped molecular laboratory. Our qPCR-based test is highly recommended for molecular diagnostics of idiopathic short stature and allied disorders.

scholarly journals Clinical and Molecular Evaluation of SHOX/PAR1 Duplications in Léri-Weill Dyschondrosteosis (LWD) and Idiopathic Short Stature (ISS)

2011 ◽  
Vol 96 (2) ◽  
pp. E404-E412 ◽  
Author(s):  
S. Benito-Sanz ◽  
E. Barroso ◽  
D. Heine-Suñer ◽  
A. Hisado-Oliva ◽  
V. Romanelli ◽  
...  
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
Copy Number ◽  
Clinical Manifestations ◽  
Idiopathic Short Stature ◽  
Pseudoautosomal Region ◽  
Height Gain ◽  
Multiple Copies ◽  
Copy Number Changes ◽  
Design And Methods

abstract Context: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. Objective: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. Design and Methods: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. Results: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5′ flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. Conclusion: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

scholarly journals Cytogenetic and Molecular Genetic Characterization of Children with Short Stature / Citogenetska in Molekularno Genetska Opredelitev Nizke Rasti Pri Otrocih

2015 ◽  
Vol 54 (2) ◽  
pp. 98-102 ◽  
Author(s):  
Tinka Hovnik ◽  
Darja Šmigoc Schweiger ◽  
Primož Kotnik ◽  
Jernej Kovač ◽  
Tadej Battelino ◽  
...  
Keyword(s):  
Short Stature ◽  
Gene Deletion ◽  
Mutation Screening ◽  
Molecular Genetic ◽  
Point Mutations ◽  
Idiopathic Short Stature ◽  
Fish Analysis ◽  
Coding Region ◽  
Exon 2 ◽  
Shox Gene

Abstract Background. The deficiency of SHOX gene (short stature homeobox-containing gene) has been recognized as the most frequent monogenetic cause of short stature. SHOX gene has been associated with short stature in Turner syndrome and Leri Weill dyschondrosteosis as well with non-syndromic idiopathic short stature. The aim of this study was to determine the frequency of SHOX deletions and mutations in a cohort of Slovenian children with short stature, and to delineate indications for routine SHOX gene mutation screening. Methods and results. 40 selected subjects with idiopathic short stature were screened for entire SHOX gene deletion and for mutations in the SHOX gene coding region (exon 2 to 6), together with sequences flanking the exon-intron boundaries. FISH analysis on metaphase and interphase spreads revealed no entire gene deletion. Additionally, no pathogenic point mutations or smaller deletion/duplications were identified in this study group. Conclusions. SHOX gene deletions and point mutations are not a common cause of idiopathic short stature in a cohort of Slovenian children with short stature. Therefore, the frequency of SHOX mutations must be much lower as expected based on the reported data.

scholarly journals Screening of SHOX gene sequence variants in Saudi Arabian children with idiopathic short stature

2017 ◽  
Vol 60 (10) ◽  
pp. 327 ◽  
Author(s):  
Abdulla A. Alharthi ◽  
Ehab I. El-Hallous ◽  
Iman M. Talaat ◽  
Hamed A. Alghamdi ◽  
Matar I. Almalki ◽  
...  
Keyword(s):  
Short Stature ◽  
Gene Sequence ◽  
Saudi Arabian ◽  
Idiopathic Short Stature ◽  
Sequence Variants ◽  
Shox Gene

scholarly journals Investigation of SHOX Gene Mutations in Turkish Patients with Idiopathic Short Stature

2016 ◽  
Vol 8 (2) ◽  
pp. 144-149 ◽  
Author(s):  
Kenan Delil ◽  
Halil Gürhan Karabulut ◽  
Bülent Hacıhamdioğlu ◽  
Zeynep Şıklar ◽  
Merih Berberoğlu ◽  
...  
Keyword(s):  
Short Stature ◽  
Gene Mutations ◽  
Idiopathic Short Stature ◽  
Shox Gene ◽  
Turkish Patients

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

2020 ◽  
Vol 33 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Anil Kumar ◽  
Vandana Jain ◽  
Madhumita Roy Chowdhury ◽  
Manoj Kumar ◽  
Punit Kaur ◽  
...  
Keyword(s):  
Growth Factor ◽  
Short Stature ◽  
Serum Insulin ◽  
Significant Proportion ◽  
Idiopathic Short Stature ◽  
Insulin Like Growth Factor ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.

scholarly journals SHOX gene and conserved noncoding element deletions/duplications in C olombian patients with idiopathic short stature

2013 ◽  
Vol 2 (2) ◽  
pp. 95-102 ◽  
Author(s):  
Gloria Tatiana Vinasco Sandoval ◽  
Giovanna Carola Jaimes ◽  
Mauricio Coll Barrios ◽  
Camila Cespedes ◽  
Harvy Mauricio Velasco
Keyword(s):  
Short Stature ◽  
Idiopathic Short Stature ◽  
Shox Gene

scholarly journals Leri-Weill dyschondrosteosis: An under-recognised cause of short stature

2009 ◽  
Vol 13 (1) ◽  
Author(s):  
E G Lemire ◽  
S Wiebe
Keyword(s):  
Differential Diagnosis ◽  
Short Stature ◽  
Pediatric Population ◽  
Chromosome Analysis ◽  
Pseudoautosomal Region ◽  
Radiographic Findings ◽  
Shox Gene ◽  
Skeletal Dysplasias ◽  
Y Chromosomes ◽  
Heterozygous Carriers

Short stature is a frequent presenting problem in the pediatric population. Various causes including endocrinopathies, skeletal dysplasias, dysmorphic syndromes and malabsorption have been implicated. In girls with short stature, Turner syndrome is frequently considered in the differential diagnosis and can easily be ruled out with chromosome analysis. However, it is not uncommon for a child to have no identifiable cause of their short stature. ?FOR Advances in the field of genetics have estimated that about 2% of idiopathic short stature is related to haploinsufficiency of the Short stature homeobox (SHOX) gene, which is found on the short arm of the X and Y chromosomes in the pseudoautosomal region. Heterozygous carriers of SHOX mutations may be minimally affected or may present with disproportionate short stature, Madelung deformity and other radiographic findings as in Leri-Weill dyschondrosteosis (LWD). In this article, we report on a 14-year old girl with mesomelic short stature and bilateral Madelung deformities caused by LWD and describe the radiographic findings.

Detection of SHOX gene deletions in Egyptian children with idiopathic short stature using FISH

Meta Gene ◽  
2020 ◽  
Vol 24 ◽  
pp. 100697
Author(s):  
Amr Shujaa-Addin ◽  
Mervat Hashish ◽  
Nahla Nazmy ◽  
Amany Srour ◽  
Ebtesam Abdalla
Keyword(s):  
Short Stature ◽  
Idiopathic Short Stature ◽  
Gene Deletions ◽  
Shox Gene ◽  
Egyptian Children
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