Transcriptional hallmarks of Noonan syndrome in peripheral blood mononuclear cells

Noonan syndrome (NS) is an autosomal dominant syndrome characterized by a distinctive facial appearance, heart defects and skeletal abnormalities, rarely associated with mental retardation or juvenile myelomonocytic leukemia. The majority of germline mutations responsible for this disorder are in the PTPN11 and SOS1 genes encoding proteins of the Ras-MAPK pathway, which regulates cell proliferation, differentiation and senescence by controlling gene expression. To investigate the transcriptional consequences of these mutations, we performed Global mRNA Expression Profiling (GEP) with Illumina oligonucleotide microarrays on Peripheral Blood Mononuclear Cells (PBMCs), a target tissue of the syndrome. In detail, we analyzed 23 samples from molecularly defined NS patients (17 with PTPN11 and 6 with SOS1 mutation), and 20 samples from age- and sex-matched controls. Out of over 20,000 genes analyzed, 5,254 passed a statistical filter for reliable signal detection and for not being correlated with age, sex, or differential leucocyte count. Subsequently, t-test and signal- to-noise ratio were used to select genes differentially expressed between control samples and NS cases, all together or subdivided in PTPN11 and SOS1 subgroups. Interestingly, GEP analysis highlighted a transcriptional profile specifically associated to the mutational status of NS samples. Both PTPN11 and SOS1 subgroups were well distinguished from control samples, however displaying clearly distinct patterns of gene expression, not consistent with a homogeneous generic NS group. These data provide initial evidence of a high potential for PBMCs GEP analysis to dissect at transcriptional level the molecular complexity of the inherited developmental disorders of the Ras-MAPK pathway.