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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Eur+J+Hum+Genet 2017 ; 25 (4): 509-11 Nephropedia Template TP
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Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome #MMPMID28098151
Mason-Suares H; Toledo D; Gekas J; Lafferty KA; Meeks N; Pacheco MC; Sharpe D; Mullen TE; Lebo MS
Eur J Hum Genet 2017[Apr]; 25 (4): 509-11 PMID28098151show ga
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.