Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome.
Document Type
Article
Publication Title
European journal of human genetics : EJHG
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.
First Page
509
Last Page
511
DOI
10.1038/ejhg.2016.202
Publication Date
4-1-2017
Recommended Citation
Mason-Suares H, Toledo D, Gekas J, Lafferty KA, Meeks N, Pacheco MC, Sharpe D, Mullen TE, Lebo MS. Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome. Eur J Hum Genet. 2017 Apr;25(4):509-511. doi: 10.1038/ejhg.2016.202. Epub 2017 Jan 18. PMID: 28098151; PMCID: PMC5386422.