Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novelSHOXenhancer

Benito‐Sanz, Sara; Royo, José Luis; Barroso, Eva; Paumard‐Hernández, Beatriz; Barreda-Bonis, Ana C; Liu, Pengfei; Gracía, Ricardo; Lupski, James R.; Campos-Barros, Ángel; Gómez-Skármeta, José Luis; Heath, Karen E.

doi:10.1136/jmedgenet-2011-100678

Cited by 63 publications

(103 citation statements)

References 43 publications

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“…Normal DNA doses were classified as showing ratios of 0.65-1.35, whereas deletions or duplications were classified as having a ratio <0.65 or >1.35, respectively. The used MLPA Kit is able to detect deletions upstream of the SHOX gene in the enhancer domain as recently reported [7]. …”

Section: Methodsmentioning

confidence: 99%

“…More than 380 different intragenic mutations in the SHOX gene - predominately missense mutations - have been identified, distributed throughout the coding regions of the gene [2,3,4]. In addition, deletions about 50-250 kb downstream of the SHOX gene in the enhancer domain have also been reported with short stature and Léri-Weill dyschondrosteosis [5,6] as well as deletions encompassing upstream of the SHOX gene in the enhancer domain [7]. SHOX encodes a transcription factor that may play a role in chondrocyte function in the growth plate as a regulator of cellular proliferation and differentiation [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Short Stature before Puberty: Which Children Should Be Screened for SHOX Deficiency?

Wolters

Lass²,

Wünsch³

et al. 2013

Horm Res Paediatr

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Objective: We studied the prevalence of deficiency in the short stature homeobox containing gene (SHOX) in prepubertal short-statured children and analyzed the clinical and radiological signs. Methods: Screening for SHOX deficiency was performed in 449 prepubertal short-statured children (54% females, aged 4-10 years) by direct sequencing and multiplex ligation probe-dependent amplification. Children with SHOX deficiency were compared to 1:2 age- and gender-matched prepubertal children without SHOX deficiency with respect to left-hand radiographs and anthropometrics including different ratios to height and proposed scores. Results: We identified 22 (4.9%) patients with SHOX deficiency (64% point mutations). Children with SHOX deficiency demonstrated a mesomelic shortening of extremities. Lower leg lengths but not forearm length was reduced in children <8 years with SHOX deficiency. 36% of all children and none of the children <8 years with SHOX deficiency demonstrated any typical radiologic sign. Increased sitting height-to-height ratio and decreased extremities-to-trunk ratio demonstrated the best positive and negative predictive values to identify SHOX deficiency. Conclusions: Screening for SHOX deficiency seems rational, especially in children with increased sitting height-to-height ratio or decreased extremities-to-trunk ratio. These criteria were also valid in young children.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Short Stature before Puberty: Which Children Should Be Screened for SHOX Deficiency?

Wolters

Lass²,

Wünsch³

et al. 2013

Horm Res Paediatr

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“…In about two-thirds of cases LWD is caused by intragenic point mutations or deletions of the complete coding sequence of SHOX, and in one-third of cases by deletions in the enhancer sequences in the 3 0 -or 5 0 -flanking region of SHOX, leaving the gene itself intact (11). A duplication of SHOX would be expected to be associated with tall stature.…”

Section: Introductionmentioning

confidence: 99%

The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

Donze¹,

Meijer²,

Kant³

et al. 2015

European Journal of Endocrinology

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Objective: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. Design: In this retrospective multi-center study (2002( -March 2014 clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). Results: Patients with SEDs showed similar HtSDS to patients with SHI (K2.3 and K2.6, respectively, PZ0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P!0.01) and extremities/trunk ratio 2.57 vs 2.43 (PZ0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (nZ3) was similar to the other groups. Conclusions: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.

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“…1). This corresponds to the CNE7-8 described by Chen et al in 2009 [6], mainly on the probes ‘L05099' and ‘L15507' (kit MLPA SHOX P018F1 SALSA), and occasionally ‘L20175', covering a region fitting exactly with the recurrent deletion initially described by Benito-Sanz et al in 2012 [34]. They observed that this copy number variation was not observed in 334 Spanish normal stature individuals and neither reported in the Database of Genomic Variants nor in the 1,000 Genomes Project, thus suggesting that this deletion is pathogenic.…”

Section: Discussionmentioning

confidence: 57%

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population

Auger¹,

Baptiste

Benabbad

et al. 2016

Horm Res Paediatr

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Background: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. Methods: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. Results: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. Conclusions: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.

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Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novelSHOXenhancer

Cited by 63 publications

References 43 publications

Short Stature before Puberty: Which Children Should Be Screened for SHOX Deficiency?

Short Stature before Puberty: Which Children Should Be Screened for SHOX Deficiency?

The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

Genotype-Phenotype Relationship in Patients and Relatives with <b><i>SHOX</i></b> Region Anomalies in the French Population

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