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.
| Original language | English |
|---|---|
| Pages (from-to) | 349-357 |
| Number of pages | 9 |
| Journal | Genetics and Molecular Biology |
| Volume | 39 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Jul 1 2016 |
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Keywords
- 1p13.2 deletion
- Noonan syndrome type 6
- NRAS gene
- RASopathy
- Unmasking heterozygosity
ASJC Scopus subject areas
- Molecular Biology
- Genetics
Cite this
1p13.2 deletion displays clinical features overlapping noonan syndrome, likely related to NRAS gene haploinsufficiency. / 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.
In: Genetics and Molecular Biology, Vol. 39, No. 3, 01.07.2016, p. 349-357.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 1p13.2 deletion displays clinical features overlapping noonan syndrome, likely related to NRAS gene haploinsufficiency
AU - Linhares, Natália Duarte
AU - Freire, Maíra Cristina Menezes
AU - Cardenas, Raony Guimarães Corrêa do Carmo Lisboa
AU - Pena, Heloisa Barbosa
AU - Lachlan, Katherine
AU - Dallapiccola, Bruno
AU - Bacino, Carlos
AU - Delobel, Bruno
AU - James, Paul
AU - Thuresson, Ann Charlotte
AU - Annerén, Göran
AU - Pena, Sérgio D J
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - 1p13.2 deletion
KW - Noonan syndrome type 6
KW - NRAS gene
KW - RASopathy
KW - Unmasking heterozygosity
UR - http://www.scopus.com/inward/record.url?scp=84984843673&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984843673&partnerID=8YFLogxK
U2 - 10.1590/1678-4685-GMB-2016-0049
DO - 10.1590/1678-4685-GMB-2016-0049
M3 - Article
AN - SCOPUS:84984843673
VL - 39
SP - 349
EP - 357
JO - Genetics and Molecular Biology
JF - Genetics and Molecular Biology
SN - 1415-4757
IS - 3
ER -