Mason-Suares Heather, Toledo Diana, Gekas Jean, Lafferty Katherine A, Meeks Naomi, Pacheco M Cristina, Sharpe David, Mullen Thomas E, Lebo Matthew S
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.
Eur J Hum Genet. 2017 Apr;25(4):509-511. doi: 10.1038/ejhg.2016.202. Epub 2017 Jan 18.
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.
一些RAS-MAPK通路基因（包括PTPN11和NRAS）中的功能获得性变异与RAS病和/或获得性血液系统恶性肿瘤相关，最显著的是青少年骨髓单核细胞白血病（JMML）。除了极少数例外情况，导致RAS病的种系变异谱与孤立性JMML中鉴定出的体细胞变异并不重叠。对这些变异的比较研究表明，JMML变异具有更强的功能获得性活性。由于JMML变异尚未被鉴定为种系缺陷，且对蛋白质功能有更大影响，因此有人推测它们会导致胚胎致死。在此，我们在4例患有严重产前或新生儿期致死性努南综合征的病例中鉴定出3种变异，这些变异此前仅在孤立的体细胞JMML和其他散发性癌症中被鉴定出。这些病例支持了这样一种假说，即这些功能获得性更强的变异很少能与生命兼容。
