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European Journal of Human Genetics (2017) 25, 823831& 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/17 http://www.nature.com/ejhg
Web End =www.nature.com/ejhg
Franziska Altmller1,2,31, Christina Lissewski1,31, Debora Bertola3,4, Elisabetta Flex5, Zornitza Stark6, Stephanie Spranger7, Gareth Baynam8,9,10,11,12,13,14, Michelle Buscarilli3, Sarah Dyack15, Jane Gillis16,
Helger G Yntema17, Francesca Pantaleoni18, Rosa LE van Loon19, Sara MacKay20, Kym Mina21,22, Ina Schanze1, Tiong Yang Tan23,24, Maie Walsh23, Susan M White23,24, Marena R Niewisch25, Sixto Garca-Miar26,
Diego Plaza27, Mohammad Reza Ahmadian28, Hlne Cav29,30, Marco Tartaglia18,32 and Martin Zenker*,1,32
RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features tting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G4A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G4C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.
European Journal of Human Genetics (2017) 25, 823831; doi:http://dx.doi.org/10.1038/ejhg.2017.65
Web End =10.1038/ejhg.2017.65; published online 3 May 2017
INTRODUCTION
More than three decades ago, the Rat Sarcoma Virus (RAS) genes were rst described and identied as key players in tumorigenesis. Harvey-, Kirsten- and neuroblastoma-RAS (HRAS, KRAS, and NRAS) encode for the three highly homologous members of the mammalian RAS subfamily of small monomeric GTPases.1 These membrane-bound proteins bind to guanine...