ACTN1-related Macrothrombocytopenia: A Novel Entity in the Progressing Field of Pediatric Thrombocytopenia

Boutroux, Hélène; David, Bianca; Guéguen, Paul; Frange, Pierre; Vincenot, Anne; Leverger, Guy; Favier, Rémi

doi:10.1097/mph.0000000000000885

Cited by 12 publications

(10 citation statements)

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“…In 2013, six different mutations of ACTN1 were identified in 13 unrelated families with IMTP, which indicated that ACTN1 was one of the genetic lesions in IMTP (12). At present, thrombocytopenia caused by pathogenic variants in ACTN1 gene has been classified to ACTN1-related thrombocytopenia (15). To date, approximately 44 mutations of ACTN1 have been detected in IMTP patients.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Values for the red blood line were normal; however, there was a measureable increase in reticulocytes (18 promille, norm 3-13 promille) at the date of investigation. The father showed normal platelet count (209 x10 9 ) and mean platelet volume (10.5 fL). Platelet counts for the sisters of the IP (S1 and S2) were 84 x10 9 and 106 x10 9 , respectively.…”

Section: Case Presentationmentioning

confidence: 98%

“…The father showed normal platelet count (209 x10 9 ) and mean platelet volume (10.5 fL). Platelet counts for the sisters of the IP (S1 and S2) were 84 x10 9 and 106 x10 9 , respectively. Platelet size was not measurable in automatic cell count systems.…”

Section: Case Presentationmentioning

confidence: 98%

“…The amino acid substitution (p.Arg46Trp) caused by the variant has been described as autosomal dominant pathogenic variant associated with ACTN1-RT. The c.136C>T (p.R46W) alteration co-segregated with disease in several unrelated families with inherited thrombocytopenia and platelet macrocytosis [7][8][9][10]. In addition, an alteration affecting the same codon, p.R46Q, were observed in two additional unrelated families with macrothrombocytopenia [4,11].…”

Section: Case Presentationmentioning

confidence: 99%

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Platelet Storage Pool Disease in a Family with Thrombocytopenia and a Pathogenic Variant in the α-Actinin Encoding Gene ACTN1

2023

Ann Case Report

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ACTN1-related thrombocytopenia (ACTN1-RT) is an inherited platelet disorder, normally associated with moderate/ mild macrothrombocytopenia and a mild bleeding diathesis. Whereas immunofluorescence studies describing the cytoskeleton organization have been reported several times, expression analyses of platelet CD62-P and CD63 using flow cytometry have rarely been performed. We report on familial thrombocytopenia, i.e. four patients -mother and three daughters with moderate/ mild thrombocytopenia who were identified as having a pathogenic variant (p.Arg46Trp) in ACTN1. Interestingly, in two of the four patients, flow cytometry analysis showed a profound decrease in surface expression of platelet activation markers CD62-P and CD63. The other two patients showed a mild reduction with different concentrations of thrombin and reached normal exposure after activation with 1 U/mL thrombin. Reduced expression of CD62-P and CD63 is hinting to an α-and δ-storage pool disease (α-/δ-SPD), respectively. Whereas a CD62-P reduction has been previously reported once, this -to our knowledge -is the first report of a CD63 reduction in association with an ACTN1-RT. Patients with platelet SPD are at higher risk for bleeding problems, especially after trauma or surgery. In summary, comprehensive investigation, including molecular genetic and platelet function analysis is important to classify the individual platelet defect. This may help to prevent unnecessary bleeding problems and to optimize perioperative management.

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“…Mutations in the coding gene ( ACTN1 ) lead to macrothrombocytopenia and disorganization of the actin filaments because the formation of platelet precursor cells is disturbed. 39…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Aspects of Inherited Platelet Disorders

et al. 2021

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Inherited platelet disorders (IPDs) constitute a large heterogeneous group of rare bleeding disorders. These are classified into: (1) quantitative defects, (2) qualitative disorders, or (3) altered platelet production rate disorders or increased platelet turnover. Classically, IPD diagnostic is based on clinical phenotype characterization, comprehensive laboratory analyses (platelet function analysis), and, in former times, candidate gene sequencing. Today, molecular genetic analysis is performed using next-generation sequencing, mostly by targeting enrichment of a gene panel or by whole-exome sequencing. Still, the biochemical and molecular genetic characterization of patients with congenital thrombocytopathias/thrombocytopenia is essential, since postoperative or posttraumatic bleeding often occurs due to undiagnosed platelet defects. Depending upon the kind of surgery or trauma, this bleeding may be life-threatening, e.g., after tonsillectomy or in brain surgery. Undiagnosed platelet defects may lead to additional surgery, hysterectomy, pulmonary bleeding, and even resuscitation. In addition, these increased bleeding symptoms can lead to wound healing problems. Only specialized laboratories can perform the special platelet function analyses (aggregometry, flow cytometry, or immunofluorescent microscopy of the platelets); therefore, many IPDs are still undetected.

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ACTN1-related Macrothrombocytopenia: A Novel Entity in the Progressing Field of Pediatric Thrombocytopenia

Abstract: We identified 11 patients with ACTN1-related macrothrombocytopenia diagnosed through pediatric probands. The aim was to underline the specificities of this entity, especially in children, and bring it to the knowledge of pediatricians.

Cited by 12 publications

References 10 publications

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

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

Platelet Storage Pool Disease in a Family with Thrombocytopenia and a Pathogenic Variant in the α-Actinin Encoding Gene ACTN1

Pathogenic Aspects of Inherited Platelet Disorders

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