Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome

Purpose We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome mostly caused by a single recurrent missense variant in SHOC2. Here we provide new data on the clinical spectrum and molecular diversity of this disorder, and functionally characterize new pathogenic variants. Methods Clinical and genomic analyses were undertaken alongside functional validation studies based on in silico, in vitro and in vivo assessment of four novel pathogenic variants. Public and newly collected clinical data were utilized to profile the disorder. Results The clinical phenotype of six unrelated individuals carrying novel pathogenic SHOC2 variants was delineated. A recognizable craniofacial phenotype in addition to ectodermal features and cognitive deficits were the most consistent manifestations in these subjects. An overall clinical homogeneity for the disorder was outlined. In silico, in vitro and in vivo characterization of these variants consistently documented an activating behaviour on SHOC2 function and MAPK signaling. Conclusion Our findings expand the molecular spectrum of pathogenic SHOC2 variants, and provide a more accurate picture of the phenotypic expression associated with variants in this gene. Finally, their functional characterization provides consistent evidence for their activating role on MAPK signaling.