Case Report: Exome Sequencing Identified a Novel Frameshift Mutation of α-Actin 1 in a Chinese Family With Macrothrombocytopenia and Mild Bleeding

Abstract

Inherited macrothrombocytopenia (IMTP) is a rare disorder characterized by a reduced platelet count and abnormally large platelets. The main clinical symptom of IMTP is mild bleeding in some patients. At present, more than 30 genes have been identified in patients with syndromic and non-syndromic IMTP. In this study, a 3-year-old boy and his mother who presented with mild epistaxis and/or gingival bleeding were diagnosed as having IMTP. Wen then selected whole sequencing to explore the genetic lesion of the patients. After data filtering and mutation validation, a novel frameshift mutation (NM_001130004: c.398_399insTGCG, p.F134AfsX60) of α-actin 1 (ACTN1) was identified in the proband and his mother but absent in other unaffected individuals. Previous studies have proven that mutations in ACTN1 may lead to IMTP with mild to absent bleeding phenotype. The novel mutation, resulting in a truncated protein in exon 4 of the ACTN1 gene, was absent in the public database, such as 1000G and genomAD. Further Western blot revealed that the expression of α-actin 1 in the proband was decreased overtly, which indicated that the novel frameshift mutation may induce non-sense-mediated mRNA decay. In summary, this study not only broadened the variants spectrum of ACTN1 gene, which may contribute to the genetic counseling of IMTP, but also confirmed the diagnosis of IMTP, which may help the management and prognosis for the family members.

The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia

“…In this study, the same rare variant mentioned above (rs117672662) was linked to alteration in mean platelet volume and platelet distribution width, while a different, more common variant was associated with mean platelet volume, albeit with a smaller effect size. Finally, a case of ACTN1-linked CMTP involving a frameshift mutation in ACTN1 has recently been reported [90]. This mutation is expected to cause production of a severely truncated protein and decreased levels of intact actinin-1 were reported.…”

“…Subsequently, these and additional novel mutations were identified in other patient cohorts. A review in 2017 catalogued 20 mutations [4] and more recent studies have brought the total number of different CMTP-causing actinin-1 mutations identified to approximately 40 [86][87][88][89][90]. With one exception (Luo 21; see below), these are all missense mutations that change a single amino acid within the actinin-1 protein, and all appear to be inherited in a dominant fashion.…”