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1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency

1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.
1415-4757
349-357
Linhares, Natália Duarte
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Freire, Maíra Cristina Menezes
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Cardenas, Raony Guimarães Corrêa do Carmo Lis
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Pena, Heloisa Barbosa
a8eb2e3f-bea2-46ff-92a0-808cf1406bbd
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Dallapiccola, Bruno
dcdfadf2-21dc-49d6-8b54-d5f6e994d200
Bacino, Carlos
4e6b4141-a3cc-411b-b58b-9aa38a52b2b8
Delobel, Bruno
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James, Paul
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Thuresson, Ann-Charlotte
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Annerén, Göran
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Pena, Sérgio D.J.
a24e6d9a-ee82-4959-a345-70472c52fec4
Linhares, Natália Duarte
27d0e266-dfe1-4e42-a93a-510939c4f18d
Freire, Maíra Cristina Menezes
c6b6dd25-1668-4701-8a69-6236cf1c13ab
Cardenas, Raony Guimarães Corrêa do Carmo Lis
0b127c4f-6495-4afc-b11a-28e261329ad8
Pena, Heloisa Barbosa
a8eb2e3f-bea2-46ff-92a0-808cf1406bbd
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Dallapiccola, Bruno
dcdfadf2-21dc-49d6-8b54-d5f6e994d200
Bacino, Carlos
4e6b4141-a3cc-411b-b58b-9aa38a52b2b8
Delobel, Bruno
5b811e86-8e33-425f-9a48-0d781bbc83f9
James, Paul
ca41caad-4a55-4fe4-9b7a-0b2b4d9a5917
Thuresson, Ann-Charlotte
13573564-37e6-43d5-902f-704d7ba0cd90
Annerén, Göran
211e922e-22c9-4def-b2a3-0b94f25f00b5
Pena, Sérgio D.J.
a24e6d9a-ee82-4959-a345-70472c52fec4

Linhares, Natália Duarte, Freire, Maíra Cristina Menezes, Cardenas, Raony Guimarães Corrêa do Carmo Lis, Pena, Heloisa Barbosa, Lachlan, Katherine, Dallapiccola, Bruno, Bacino, Carlos, Delobel, Bruno, James, Paul, Thuresson, Ann-Charlotte, Annerén, Göran and Pena, Sérgio D.J. (2016) 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency. [in special issue: Special Series of Articles - 60 Years of The Brazilian Society of Genetics] Genetics and Molecular Biology, 39 (3), 349-357. (doi:10.1590/1678-4685-GMB-2016-0049).

Record type: Article

Abstract

Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

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Accepted/In Press date: 9 May 2016
e-pub ahead of print date: 4 August 2016
Published date: September 2016
Organisations: Human Development & Health

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Local EPrints ID: 402671
URI: http://eprints.soton.ac.uk/id/eprint/402671
ISSN: 1415-4757
PURE UUID: a0de0c43-ba23-45f0-9d26-1418fc0cbb7f

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Date deposited: 14 Nov 2016 13:03
Last modified: 06 Oct 2020 20:23

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Contributors

Author: Natália Duarte Linhares
Author: Maíra Cristina Menezes Freire
Author: Raony Guimarães Corrêa do Carmo Lis Cardenas
Author: Heloisa Barbosa Pena
Author: Katherine Lachlan
Author: Bruno Dallapiccola
Author: Carlos Bacino
Author: Bruno Delobel
Author: Paul James
Author: Ann-Charlotte Thuresson
Author: Göran Annerén
Author: Sérgio D.J. Pena

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