title: Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome.
abstract: Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal. Here we identified three variants, which have previously only been identified in isolated somatic JMML and other sporadic cancers, in four cases with a severe pre- or neo-natal lethal presentation of Noonan syndrome. These cases support the hypothesis that these stronger gain-of-function variants are rarely compatible with life.
authors.affiliation: Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.|Departments of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mason-Suares
authors.affiliation: Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Toledo
authors.affiliation: Department of Medical Biology, Le CHU de Québec, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gekas
authors.affiliation: Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Lafferty
authors.affiliation: Section of Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Meeks
authors.affiliation: Department of Pathology, Children's Hospitals & Clinics of MN, Saint Paul, MN, USA.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Pacheco
authors.affiliation: Maternal Fetal Medicine, Riverside Methodist Hospital, Columbus, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sharpe
authors.affiliation: Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mullen
authors.affiliation: Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.|Departments of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Matthew S
authors.identifier: 0000-0002-9733-5207
authors.initials: MS
authors.lastname: Lebo
mesh_terms: D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D011247:Pregnancy; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human