ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization

Abstract

Key Points ACTN1 mutations were identified in 10 of 239 families with inherited thrombocytopenia of unknown origin. ACTN1-related thrombocytopenia is characterized by mild thrombocytopenia with platelet macrocytosis and low risk for bleeding.

Familial macrothrombocytopenia due to a double mutation in cis in the alpha‐actinin 1 gene (ACTN1), previously considered to be chronic immune thrombocytopenic purpura

“…ACTN1 ‐macrothrombocytopenia is usually characterized by a moderate thrombocytopenia with a platelet anisocytosis and mild bleeding tendency, as in our family. The relative high IPF in this family suggests increased platelet destruction, rather than solely reduced production problem as considered previously . The normal thrombopoietin values, which are inversely related to megakaryocyte count, support this thought .…”

“…Genetic testing using Illumina NGS was performed in all the family members targeting 89 genes known to be involved in the primary hemostasis (TRO02vs16.1). The index patient and his mother showed two missense mutations in the ACTN1 gene, a gene associated with macrothrombocytopenia . The ACTN1 mutations were found in exon 8 (c.698C > T) and exon 19 (c.2353G > A), predicting to cause a proline (P) to leucine (L) substitution at amino acid position 233 p.(P233L), and an aspartic acid (D) to asparagine (N) substitution at amino acid position 785 p.(D785N), respectively.…”

“…Mutations within ACTN1 , which inherits autosomal dominantly, cause a disturbed thrombopoiesis, i.e., abnormal proplatelet formation from megakaryocytes and the production of large platelets . It has been stated that ACTN1 is involved in 5% of the inherited thrombocytopenias . Furthermore, variants of ACTN1 have been identified through GWAS as being responsible for lower platelet counts …”

Diagnostic biomarker for ACTN1 macrothrombocytopenia

“…1 Recently, mutations in ACTN1, the gene encoding a-actinin-1, have been found to be the next prevalent cause for congenital macrothrombocytopenia and should be considered in the differential diagnosis. [3][4][5] We herein propose a diagnostic screening test for ACTN1 macrothrombocytopenia.…”

“…Accordingly, a molecular genetic analysis is only available for the diagnosis and there is an unmet need for the development of a diagnostic test for clinical diagnostic practice. [3][4][5] Peripheral blood smears from controls (n 5 4) and patients with MYH9 disorders (n 5 2) and ACTN1 macrothrombocytopenia (n 5 3) were double-stained with anti-a-actinin-1 antibody (sc-17829; Santa Cruz Biotechnology) and anti-NMMHCIIA antibody (BT561; Biomedical Technologies) and examined using a BX50 fluorescence microscope with a UPlanApo 1003/1.35 objective lens (Olympus).…”