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.

FUNCTIONAL ANALYSIS OF NEW GENETIC VARIANTS IDENTIFIED IN GENES OF INHERITED THROMBOCYTOPENIA

FONTANA, GIORGIA
2021

Abstract

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.
SAVOIA, ANNA
33
2019/2020
Settore MED/03 - Genetica Medica
Università degli Studi di Trieste
File in questo prodotto:
File Dimensione Formato  
Tesi dottorato Fontana Giorgia definitiva.pdf

embargo fino al 26/03/2023

Descrizione: FUNCTIONAL ANALYSIS OF NEW GENETIC VARIANTS IDENTIFIED IN GENES OF INHERITED THROMBOCYTOPENIA
Tipologia: Documento in Versione Editoriale
Licenza: Digital Rights Management non definito
Dimensione 2.17 MB
Formato Adobe PDF
2.17 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2983831
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact