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.