Rare variants in<i>SOS2</i>and<i>LZTR1</i>are associated with Noonan syndrome

Yamamoto, Guilherme Lopes; Aguena, Meire; Gos, Monika; Hung, Christina; Pilch, Jacek; Fahiminiya, Somayyeh; Abramowicz, Anna; Cristian, Ingrid; Buscarilli, Michelle; Naslavsky, Michel Satya; Malaquias, Alexsandra C.; Zatz, Mayana; Bodamer, Olaf A.; Majewski, Jacek; Jorge, Alexander A. L.; Pereira, Alexandre C.; Kim, Chong; Passos‐Bueno, Maria Rita; Bertola, Débora Romeo

doi:10.1136/jmedgenet-2015-103018

Cited by 216 publications

(207 citation statements)

References 27 publications

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“…The mechanism by which mutations in LZTR1 causes NS is still unknown. Yamamoto et al [18] suggested that missense heterozygous variants in LZTR1 may cause dysregulation of the RAS/MAPK pathway by increasing ERK signaling through a loss of tumor suppressor function.…”

Section: Discussionmentioning

confidence: 99%

“…Two of these patients had LZTR1 variants (p.R237Q and p.A249P) which were not considered as responsible for the NS phenotype, since the authors considered LZTR1 as a gene already associated with DiGeorge syndrome. In 2015, Yamamoto et al identified rare variants of LZTR1 using whole-exome sequencing in 6/50 Brazilian probands (p.G248R, p. R284C, p.H287Y, p.Y119C, p.I647Vand p.F447L) and one Polish family ( p.S247N ) with NS and lacking mutation in the known NS genes [18]. Two of these variants were considered nonpathogenic because of their presence in unaffected relatives (p.F447L) or the weak of in silico pathogenicity prediction (p.I647V).…”

Section: Discussionmentioning

confidence: 99%

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Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Ghedira¹,

Kraoua²,

Lagarde³

et al. 2017

Biol Med

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Ghedira¹,

Kraoua²,

Lagarde³

et al. 2017

Biol Med

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“…PTPN11 mutations (40%‐50%), SOS1 mutations (10%‐20%), RAF1 (3%‐17%), and RIT1 (9%) are common, followed by KRAS , NRAS , BRAF , SHOC2 , MAP2K1 , CBL, LZTR1, SOS2, RRAS, and CDC42 1, 2, 3, 4, 5, 6, 7, 8, 9…”

Section: Introductionmentioning

confidence: 99%

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

Tamura

Uemura

Matsubara

et al. 2018

Clinical Case Reports

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“…6 Several other genes involved in the RAS/MAPK cascade were later found to explain smaller subgroups of NS, with loose genotypephenotype correlations: KRAS (OMIM 190070), SOS1 (OMIM 182530), RAF1 (OMIM 164760), NRAS (OMIM 164790), SHOC2 (OMIM 602775), and CBL (OMIM 165360). 7 RIT1 (Ras-like without CAAX 1; OMIM 609591) was identified in 2013, 8 and more recently, mutations in RRAS 9 (OMIM 165090), RASA2 10 (OMIM 601589), SOS2 11,12 (OMIM 601247), and LZTR1 11 (OMIM 600774) have added further heterogeneity to the NS landscape. Rarely, NS has also been reported in patients with mutations in the CFC (cardiofaciocutaneous syndrome) genes BRAF, 11 MAP2K1, and MAP2K2.…”

Section: Introductionmentioning

confidence: 99%

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

et al. 2016

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Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

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Rare variants inSOS2andLZTR1are associated with Noonan syndrome

Cited by 216 publications

References 27 publications

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

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