Inherited thrombocytopenias (IT) are a group of rare diseases characterized by a low platelet count (less than
150.000 / mL) and high degree of heterogeneity at both clinical and genetic point of view.
To date, mutations in at least 30 different genes have been identified, however about 50% of patients still remain
without molecular diagnosis, due to the complexity of the diagnostic framework and because many patients are
probably affected by forms of IT not characterized yet.
The spread in the last decade of next generation sequencing techniques (Next Generation Sequencing, NGS)
allow us to simultaneously analyse many candidate genes and identify thousands of variants in a single analysis.
However, understanding the effects of these variants remains a major problem in disorders such as
thrombocytopenia, which are mainly autosomal dominant diseases caused by "private" mutations, often
missense. In fact, while for "deleterious" mutations, such as large deletions, nonsense or frameshift the
relationship between the variant and their pathogenicity is often immediate due to the important structural and
functional consequences on the protein, determining the pathogenic role of a missense variant is a complex
process that requires targeted functional studies. My PhD work, carried out at the Medical Genetics laboratory of Professor Anna Savoia at Burlo Garofolo hospital in Trieste, fits into this context and consists in the pathogenicity analysis, through
functional assays, of the variants identified in three transcription factor genes (MECOM, GFI1B and
RUNX1), whose mutations are responsible for MECOM-associated syndrome, platelet - type bleeding
disorder - 17 (BDPLT17) and FPD/AML thrombocytopenia, respectively. My PhD work indicates that functional assays are essential, in combination with genetic analysis, to discriminate between pathogenic and non-pathogenic variants. This aspect is very important especially in case of diseases characterized by a wide spectrum of variants that are predicted to be of uncertain significance, as ITs.
The functional characterization of variant, in fact, allow us to provide patients correct molecular diagnoses, which
is fundamental for an appropriate therapeutic approach and a properly follow-up of patients, especially when
they are carriers of a mutation that increase the risk of developing further, even more serious, diseases.
