Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorYAMAMOTO, Guilherme Lopes
dc.contributor.authorAGUENA, Meire
dc.contributor.authorGOS, Monika
dc.contributor.authorHUNG, Christina
dc.contributor.authorPILCH, Jacek
dc.contributor.authorFAHIMINIYA, Somayyeh
dc.contributor.authorABRAMOWICZ, Anna
dc.contributor.authorCRISTIAN, Ingrid
dc.contributor.authorBUSCARILLI, Michelle
dc.contributor.authorNASLAVSKY, Michel Satya
dc.contributor.authorMALAQUIAS, Alexsandra C.
dc.contributor.authorZATZ, Mayana
dc.contributor.authorBODAMER, Olaf
dc.contributor.authorMAJEWSKI, Jacek
dc.contributor.authorJORGE, Alexander A. L.
dc.contributor.authorPEREIRA, Alexandre C.
dc.contributor.authorKIM, Chong Ae
dc.contributor.authorPASSOS-BUENO, Maria Rita
dc.contributor.authorBERTOLA, Debora Romeo
dc.date.accessioned2015-10-26T16:25:14Z
dc.date.available2015-10-26T16:25:14Z
dc.date.issued2015
dc.description.abstractBackground Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. Methods A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. Results We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. Conclusions We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.
dc.description.indexMEDLINE
dc.description.sponsorshipFAPESP [2011/17299-3]
dc.description.sponsorshipCEPID/FAPESP [98/14254-2]
dc.description.sponsorshipCNPq [302605/2013-4]
dc.description.sponsorshipNational Science Centre [UMO-2013/09/B/NZ2/03164, UMO-2011/01/D/NZ5/01347]
dc.identifier.citationJOURNAL OF MEDICAL GENETICS, v.52, n.6, p.413-421, 2015
dc.identifier.doi10.1136/jmedgenet-2015-103018
dc.identifier.eissn1468-6244
dc.identifier.issn0022-2593
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/11563
dc.language.isoeng
dc.publisherBMJ PUBLISHING GROUP
dc.relation.ispartofJournal of Medical Genetics
dc.rightsrestrictedAccess
dc.rights.holderCopyright BMJ PUBLISHING GROUP
dc.subject.otherdigeorge-syndrome
dc.subject.othersequencing data
dc.subject.othergene analysis
dc.subject.otherptpn11
dc.subject.otherschwannomatosis
dc.subject.othermutations
dc.subject.otherphenotype
dc.subject.otherdeletion
dc.subject.othercomplex
dc.subject.otherrit1
dc.subject.wosGenetics & Heredity
dc.titleRare variants in SOS2 and LZTR1 are associated with Noonan syndrome
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryPolônia
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryisopl
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisoca
hcfmusp.author.externalAGUENA, Meire:Univ Sao Paulo, Inst Biociencias, Ctr Pesquisa Genoma Humano & Celulas Tronco, BR-05403000 Sao Paulo, SP, Brazil
hcfmusp.author.externalGOS, Monika:Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland
hcfmusp.author.externalHUNG, Christina:Boston Childrens Hosp, Dept Med, Div Genet & Genom, Boston, MA USA
hcfmusp.author.externalPILCH, Jacek:Med Univ Silesia, Dept Child Neurol, Katowice, Poland
hcfmusp.author.externalFAHIMINIYA, Somayyeh:McGill Univ, Dept Human Genet, Montreal, PQ, Canada
hcfmusp.author.externalABRAMOWICZ, Anna:Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland
hcfmusp.author.externalCRISTIAN, Ingrid:Nemours Childrens Hosp Orlando, Orlando, FL USA
hcfmusp.author.externalNASLAVSKY, Michel Satya:Univ Sao Paulo, Inst Biociencias, Ctr Pesquisa Genoma Humano & Celulas Tronco, BR-05403000 Sao Paulo, SP, Brazil
hcfmusp.author.externalZATZ, Mayana:Univ Sao Paulo, Inst Biociencias, Ctr Pesquisa Genoma Humano & Celulas Tronco, BR-05403000 Sao Paulo, SP, Brazil
hcfmusp.author.externalBODAMER, Olaf:Boston Childrens Hosp, Dept Med, Div Genet & Genom, Boston, MA USA
hcfmusp.author.externalMAJEWSKI, Jacek:McGill Univ, Dept Human Genet, Montreal, PQ, Canada
hcfmusp.author.externalPASSOS-BUENO, Maria Rita:Univ Sao Paulo, Inst Biociencias, Ctr Pesquisa Genoma Humano & Celulas Tronco, BR-05403000 Sao Paulo, SP, Brazil
hcfmusp.citation.scopus169
hcfmusp.contributor.author-fmusphcGUILHERME LOPES YAMAMOTO
hcfmusp.contributor.author-fmusphcMICHELLE BUSCARILLI DE MORAES
hcfmusp.contributor.author-fmusphcALEXSANDRA CHRISTIANNE MALAQUIAS DE MOURA RIBEIRO
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.contributor.author-fmusphcALEXANDRE DA COSTA PEREIRA
hcfmusp.contributor.author-fmusphcCHONG AE KIM
hcfmusp.contributor.author-fmusphcDEBORA ROMEO BERTOLA
hcfmusp.description.beginpage413
hcfmusp.description.endpage421
hcfmusp.description.issue6
hcfmusp.description.volume52
hcfmusp.origemWOS
hcfmusp.origem.pubmed25795793
hcfmusp.origem.scopus2-s2.0-84930622528
hcfmusp.origem.wosWOS:000354952300007
hcfmusp.publisher.cityLONDON
hcfmusp.publisher.countryENGLAND
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