PMID- 26757980 OWN - NLM STAT- MEDLINE DCOM- 20170724 LR - 20181113 IS - 1476-5438 (Electronic) IS - 1018-4813 (Print) IS - 1018-4813 (Linking) VI - 24 IP - 8 DP - 2016 Aug TI - Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. PG - 1124-31 LID - 10.1038/ejhg.2015.273 [doi] AB - 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. FAU - Cave, Helene AU - Cave H AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. AD - INSERM UMR S1131, Institut Universitaire d'Hematologie, Denis Diderot Medical School, Sorbonne-Paris-Cite University, Paris, France. FAU - Caye, Aurelie AU - Caye A AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. AD - INSERM UMR S1131, Institut Universitaire d'Hematologie, Denis Diderot Medical School, Sorbonne-Paris-Cite University, Paris, France. FAU - Ghedira, Nehla AU - Ghedira N AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. AD - INSERM UMR S1131, Institut Universitaire d'Hematologie, Denis Diderot Medical School, Sorbonne-Paris-Cite University, Paris, France. FAU - Capri, Yline AU - Capri Y AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Pouvreau, Nathalie AU - Pouvreau N AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Fillot, Natacha AU - Fillot N AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Trimouille, Aurelien AU - Trimouille A AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. AD - INSERM UMR S1131, Institut Universitaire d'Hematologie, Denis Diderot Medical School, Sorbonne-Paris-Cite University, Paris, France. FAU - Vignal, Cedric AU - Vignal C AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Fenneteau, Odile AU - Fenneteau O AD - Hematology Laboratory, AP-HP - Robert Debre University Hospital, Paris, France. FAU - Alembik, Yves AU - Alembik Y AD - Department of Genetics, University Hospital, Strasbourg, France. FAU - Alessandri, Jean-Luc AU - Alessandri JL AD - Department of Genetics, University Hospital, Saint Denis de la Reunion, France. FAU - Blanchet, Patricia AU - Blanchet P AD - Department of Genetics, University Hospital, Montpellier, France. FAU - Boute, Odile AU - Boute O AD - Department of Genetics, Jeanne de Flandre University Hospital, Lille, France. FAU - Bouvagnet, Patrice AU - Bouvagnet P AD - Medico-surgical Department of Child and Adult Cardiology, Louis Pradel University Hospital, Lyon University, Bron, France. FAU - David, Albert AU - David A AD - Department of Genetics, University Hospital, Nantes, France. FAU - Dieux Coeslier, Anne AU - Dieux Coeslier A AD - Department of Genetics, Jeanne de Flandre University Hospital, Lille, France. FAU - Doray, Berenice AU - Doray B AD - Department of Genetics, University Hospital, Strasbourg, France. FAU - Dulac, Olivier AU - Dulac O AD - Department of Child Neurology, AP-HP-Necker-Enfants Malades Hospital, Paris, France. FAU - Drouin-Garraud, Valerie AU - Drouin-Garraud V AD - Department of Genetics, University Hospital, Rouen, France. FAU - Gerard, Marion AU - Gerard M AD - Department of Genetics, University Hospital, Caen, France. FAU - Heron, Delphine AU - Heron D AD - Department of Genetics, AP-HP - La Pitie-Salpetriere Hospital, Paris, France. FAU - Isidor, Bertrand AU - Isidor B AD - Department of Genetics, University Hospital, Nantes, France. FAU - Lacombe, Didier AU - Lacombe D AD - Department of Genetics, University Hospital, Bordeaux, France. FAU - Lyonnet, Stanislas AU - Lyonnet S AD - Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France. FAU - Perrin, Laurence AU - Perrin L AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Rio, Marlene AU - Rio M AD - Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France. FAU - Roume, Joelle AU - Roume J AD - Department of Genetics, Intercommunal Hospital, Poissy-St Germain en Laye, France. FAU - Sauvion, Sylvie AU - Sauvion S AD - Department of Pediatrics, AP-HP - Jean Verdier Hospital, Bondy, France. FAU - Toutain, Annick AU - Toutain A AD - Department of Genetics, University Hospital, Tours, France. FAU - Vincent-Delorme, Catherine AU - Vincent-Delorme C AD - Department of Genetics, Jeanne de Flandre University Hospital, Lille, France. FAU - Willems, Marjorie AU - Willems M AD - Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France. FAU - Baumann, Clarisse AU - Baumann C AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. FAU - Verloes, Alain AU - Verloes A AD - Department of Genetics, Assistance Publique - Hopitaux de Paris (AP-HP) - Robert Debre University Hospital, Paris, France. AD - INSERM UMR 1141, Denis Diderot Medical School, Sorbonne-Paris-Cite University, Paris, France. LA - eng PT - Journal Article DEP - 20160113 PL - England TA - Eur J Hum Genet JT - European journal of human genetics : EJHG JID - 9302235 RN - EC 3.6.1.- (RIT1 protein, human) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Adolescent MH - Adult MH - Child MH - Child, Preschool MH - Female MH - Humans MH - Leukemia, Myelomonocytic, Juvenile/*genetics/pathology MH - Male MH - *Mutation MH - Noonan Syndrome/*genetics/pathology MH - Pedigree MH - Phenotype MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology MH - ras Proteins/*genetics PMC - PMC4970687 EDAT- 2016/01/14 06:00 MHDA- 2017/07/25 06:00 PMCR- 2017/08/01 CRDT- 2016/01/14 06:00 PHST- 2014/11/22 00:00 [received] PHST- 2015/12/01 00:00 [revised] PHST- 2015/12/02 00:00 [accepted] PHST- 2016/01/14 06:00 [entrez] PHST- 2016/01/14 06:00 [pubmed] PHST- 2017/07/25 06:00 [medline] PHST- 2017/08/01 00:00 [pmc-release] AID - ejhg2015273 [pii] AID - 10.1038/ejhg.2015.273 [doi] PST - ppublish SO - Eur J Hum Genet. 2016 Aug;24(8):1124-31. doi: 10.1038/ejhg.2015.273. Epub 2016 Jan 13.