Platelet-Type Bleeding Disorder 15 and Thrombocytopenia via the ACTN1 Gene

Inherited thrombocytopenias (IT) comprise a heterogeneous group of disorders characterized by platelet counts below the lower limit of normal, i.e. below 150,000/microL (150 x 10⁹/L) in adults. Bleeding manifestations of thrombocytopenia range from mild to severe and may include excessive bruising (purpura), petechiae, prolonged bleeding from cuts or from surgical procedures, spontaneous nose bleeds, and in women, heavy menstrual flows. About half of ITs are syndromic disorders characterized by other physical and neurological anomalies, or immunodeficiencies (Balduini et al. 2013. PubMed ID: 23397552). Over 30 genes are known to be associated with ITs. Pathogenic variants in known genes are found in only about 50% of cases (Kunishima et al. 2006. PubMed ID: 16169642; Noris et al. 2017. PubMed ID: 29222283). Noris et al. divide ITs into three groups: forms characterized by only platelet deficiencies, syndromic ITs with additional congenital defects, and ITs associated with increased risk of developing additional disease such as myelodysplastic syndrome (MDS) and acute leukemia (AL) (Churpek et al. 2013. PubMed ID: 22691122). It is important to distinguish ITs from immune/idiopathic thrombocytopenias (ITP) in order to inform clinical management and identify potential at risk family members.

ACTN1-associated platelet-type bleeding disorder 15 is characterized by mild thrombocytopenia with large platelets (macrothrombocytopenia), low risk of bleeding, and anisocytosis (Kunishima et al. 2013. PubMed ID: 23434115). The prognosis for ACTN1-related thrombocytopenia diagnosis is considered good.

ACTN1-associated macrothrombocytopenia is inherited in an autosomal dominant manner (Kunishima et al. 2013. PubMed ID: 23434115). Pathogenic variants in ACTN1 accounted for 5.5% of dominant thrombocytopenia cases in a study of Japanese individuals and are the fourth most frequent cause of inherited thrombocytopenias overall (Kunishima et al. 2013. PubMed ID: 23434115; Faleschini et al. 2018. PubMed ID: 30351444). Pathogenic variants consist primarily of missense variants (Westbury et al. 2015. PubMed ID: 25949529), and no gross deletions or duplications have been reported.

ACTN1 encodes a non-muscle isoforms of α-actinin 1 found in megakaryocytes and platelets. Pathogenic variants in the ACTN1 protein affect proper subcellular localization, which leads to abnormal cytoskeletal formation (Bottega et al. 2015. PubMed ID: 25361813).

Over 30 genes are known to be associated with inherited thrombocytopenias. Pathogenic variants in known genes are found in only about 50% of cases (Kunishima and Saito. 2006. PubMed ID: 16169642; Noris et al. 2017. PubMed ID: 29222283). Pathogenic variants in ACTN1 accounted for 5.5% of dominant thrombocytopenia cases in a study of Japanese individuals and are the fourth most frequent cause of inherited thrombocytopenias overall (Kunishima et al. 2013. PubMed ID: 23434115; Faleschini et al. 2018. PubMed ID: 30351444).

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV-calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the ACTN1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).