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

• Published in: Blood Vol. 125; no. 5; pp. 869 - 872
• Main Authors: Bottega, Roberta, Marconi, Caterina, Faleschini, Michela, Baj, Gabriele, Cagioni, Claudia, Pecci, Alessandro, Pippucci, Tommaso, Ramenghi, Ugo, Pardini, Simonetta, Ngu, Loretta, Baronci, Carlo, Kunishima, Shinji, Balduini, Carlo L., Seri, Marco, Savoia, Anna, Noris, Patrizia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2015; American Society of Hematology
• Subjects: Actinin - genetics; Actinin - metabolism; Adolescent; Adult; Aged; Aged, 80 and over; Blood Platelets - metabolism; Blood Platelets - pathology; Brief Report; Case-Control Studies; Child; Child, Preschool; Female; Gene Expression; Genotype; Heterozygote; Humans; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype; Platelet Count; Platelets and Thrombopoiesis; Severity of Illness Index; Thrombocytopenia - genetics; Thrombocytopenia - metabolism; Thrombocytopenia - pathology; Thrombocytopenia - physiopathology; Thrombopoiesis - genetics; Thrombopoietin - blood
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-08-594531

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs. •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.