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Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature

Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature
Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature
Leri–Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation-dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri–Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis-regulatory DNA elements can result in a SHOX-related phenotype. © 2015 Wiley Periodicals, Inc.
SHOX, duplication, regulatory element
1552-4825
949-957
Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Baffico, Maria
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Capone, Lucia
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Vannelli, Silvia
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Iughetti, Lorenzo
8d99f43a-053e-40ad-94d2-75bfd490b2a7
Schmitt, Sébastien
7f3b6436-dc43-4651-8490-317337271260
Taylor, Emma-Jane
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Herridge, Adam A.
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Shears, Deborah
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Forabosco, Antonino
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Coviello, Domenico A.
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Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Baffico, Maria
6e1a34ea-34dd-4909-aed1-a1ab5c7fbc60
Capone, Lucia
a838fecb-dd38-48e0-b45d-0677ddc08aae
Vannelli, Silvia
b314ceb1-7d6b-4fe2-a7bd-f19c954ed3a4
Iughetti, Lorenzo
8d99f43a-053e-40ad-94d2-75bfd490b2a7
Schmitt, Sébastien
7f3b6436-dc43-4651-8490-317337271260
Taylor, Emma-Jane
15ca3766-cb76-4217-999e-ada378903d58
Herridge, Adam A.
7f500004-91f7-48dc-8774-5fcaea31102f
Shears, Deborah
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Forabosco, Antonino
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Coviello, Domenico A.
14100512-8887-4278-9f51-66a2f008492b

Bunyan, David J., Baffico, Maria, Capone, Lucia, Vannelli, Silvia, Iughetti, Lorenzo, Schmitt, Sébastien, Taylor, Emma-Jane, Herridge, Adam A., Shears, Deborah, Forabosco, Antonino and Coviello, Domenico A. (2016) Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature. American Journal of Medical Genetics: Part A, 170 (4), 949-957. (doi:10.1002/ajmg.a.37524).

Record type: Article

Abstract

Leri–Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation-dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri–Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis-regulatory DNA elements can result in a SHOX-related phenotype. © 2015 Wiley Periodicals, Inc.

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Accepted/In Press date: 4 December 2015
e-pub ahead of print date: 24 December 2015
Published date: April 2016
Keywords: SHOX, duplication, regulatory element
Organisations: Human Development & Health

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Local EPrints ID: 385472
URI: http://eprints.soton.ac.uk/id/eprint/385472
ISSN: 1552-4825
PURE UUID: 6cea65ed-dd88-46bc-8d97-d45dc8106e93

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Date deposited: 20 Jan 2016 09:50
Last modified: 15 Jul 2019 20:52

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Contributors

Author: David J. Bunyan
Author: Maria Baffico
Author: Lucia Capone
Author: Silvia Vannelli
Author: Lorenzo Iughetti
Author: Sébastien Schmitt
Author: Emma-Jane Taylor
Author: Adam A. Herridge
Author: Deborah Shears
Author: Antonino Forabosco
Author: Domenico A. Coviello

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