Thrombocytopenia Related to Defects in Platelet Cytoskeleton Regulation Genes

Introduction: Inherited thrombocytopenias (ITs) are clinically and genetically heterogeneous diseases, caused by mutations in numerous genes encoding a variety of molecules. Next-generation sequencing (NGS) is a revolutionary technique that has been providing significant breakthroughs in the molecular bases of inherited thrombocytopenias. A large group of ITs are associated with defects of proplatelet formation and platelet release. Mutations in genes, such as MYH9, ACTN1, WAS, TUBB1, and FLNA, known to encode for different components of cytoskeleton, are responsible for ITs.

Aim: Investigation of the molecular mechanisms affecting platelet cytoskeleton regulation genes with NGS.

Results: We present 6 heterozygous genetic variants in MYH9 (1), ACTN1 (3) and FLNA (2) identified in 7 index patients and family members. Patient 1 and 2 carried a known nonsense mutation p.(Arg1933Ter) in the MYH9. Patients 3 and 4 carried novel heterozygous FLNA variants: p.(Glu2257Lys) and p.(Gln1769Ter). Heterozygous variants in the ACTN1 were identified in patient 5-7 - p.(Arg46Trp), p.(Pro888Leu), p.(Ala255Val). Four were novel variants, segregating with the thrombocytopenia along the pedigrees, when family members were available and were not reported in the 1000 genomes or other databases. The 4 novel variants affected highly conserved amino acid residues and different pathogenicity prediction tools indicated deleterious effects. Clinically, most patients presented with moderately reduced platelet count and highly variable degree of bleeding symptoms - from spontaneous mucocutaneous hemorrhages, to no bleeding or only easy bruising.

Conclusions: Mutations of MYH9, ACTN1 and FLNA cause inherited thrombocytopenia characterized by widely variable phenotype that could be explained by correlations with the genotype. Molecular genetic testing combined with segregation analysis and functional assays carried out to discriminate between pathogenic and silent variants, is the only diagnostic approach to identify patients with ITs.