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

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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Main Authors: Linhares,Natália Duarte, Freire,Maíra Cristina Menezes, Cardenas,Raony Guimarães Corrêa do Carmo Lisboa, Pena,Heloisa Barbosa, Lachlan,Katherine, Dallapiccola,Bruno, Bacino,Carlos, Delobel,Bruno, James,Paul, Thuresson,Ann-Charlotte, Annerén,Göran, Pena,Sérgio D. J.
Format: Digital revista
Language:English
Published: Sociedade Brasileira de Genética 2016
Online Access:http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572016000300349
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spelling oai:scielo:S1415-475720160003003492016-08-251p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiencyLinhares,Natália DuarteFreire,Maíra Cristina MenezesCardenas,Raony Guimarães Corrêa do Carmo LisboaPena,Heloisa BarbosaLachlan,KatherineDallapiccola,BrunoBacino,CarlosDelobel,BrunoJames,PaulThuresson,Ann-CharlotteAnnerén,GöranPena,Sérgio D. J. 1p13.2 deletion Noonan syndrome type 6 NRAS gene RASopathy unmasking heterozygosity 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.info:eu-repo/semantics/openAccessSociedade Brasileira de GenéticaGenetics and Molecular Biology v.39 n.3 20162016-09-01info:eu-repo/semantics/articletext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572016000300349en10.1590/1678-4685-GMB-2016-0049
institution SCIELO
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country Brasil
countrycode BR
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access En linea
databasecode rev-scielo-br
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libraryname SciELO
language English
format Digital
author Linhares,Natália Duarte
Freire,Maíra Cristina Menezes
Cardenas,Raony Guimarães Corrêa do Carmo Lisboa
Pena,Heloisa Barbosa
Lachlan,Katherine
Dallapiccola,Bruno
Bacino,Carlos
Delobel,Bruno
James,Paul
Thuresson,Ann-Charlotte
Annerén,Göran
Pena,Sérgio D. J.
spellingShingle Linhares,Natália Duarte
Freire,Maíra Cristina Menezes
Cardenas,Raony Guimarães Corrêa do Carmo Lisboa
Pena,Heloisa Barbosa
Lachlan,Katherine
Dallapiccola,Bruno
Bacino,Carlos
Delobel,Bruno
James,Paul
Thuresson,Ann-Charlotte
Annerén,Göran
Pena,Sérgio D. J.
1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
author_facet Linhares,Natália Duarte
Freire,Maíra Cristina Menezes
Cardenas,Raony Guimarães Corrêa do Carmo Lisboa
Pena,Heloisa Barbosa
Lachlan,Katherine
Dallapiccola,Bruno
Bacino,Carlos
Delobel,Bruno
James,Paul
Thuresson,Ann-Charlotte
Annerén,Göran
Pena,Sérgio D. J.
author_sort Linhares,Natália Duarte
title 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
title_short 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
title_full 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
title_fullStr 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
title_full_unstemmed 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
title_sort 1p13.2 deletion displays clinical features overlapping noonan syndrome, likely related to nras gene haploinsufficiency
description 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.
publisher Sociedade Brasileira de Genética
publishDate 2016
url http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572016000300349
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