Glanzmann's Thrombasthenia via the ITGB3 Gene

Glanzmann's Thrombasthenia (GT) is the most commonly inherited disorder of platelet function. Extensive phenotypic variability is seen with GT where mucocutaneous bleeding episodes are the most uniform symptom. Other clinical features may include hemorrhage, easy bruising, postpartum bleeding, and menorrhagia. Platelet count and morphology are typically normal in patients with GT making diagnosis more difficult (Nurden et al. 2013). Bleeding in patients affected with GT is due to loss of the integrin receptor complex CD41, also known as GpIIb/IIIa, thereby preventing platelet binding to fibrinogen at sites of vessel injury. Onset age is directly correlated to the amount of functional CD41 integrin complex with severe cases displaying symptoms in early childhood. Platelet infusions and recombinant factor VIIa treatments have been shown to curtail symptoms (Coppola et al. 2004; Poon et al, 2004). Genetic testing is helpful for differential diagnosis of GT from other disorders displaying mucocutaneous bleeding and platelet function defects.

GT is inherited in an autosomal recessive manner through mutations in either the ITGB3 or ITGA2B genes. Mutations in ITGB3 are detected in slightly under half of patients with GT. To date, nearly 100 mutations have been described throughout the ITGB3 gene in patients with GT with missense and small deletions being most common. Missense mutations primarily disrupt αIIbβ3 integrin complex formation where small deletions typically lead to formation of a premature stop codon (Jallu et al. 2010; http://med.mssm.edu/glanzmanndb). Frequently observed mutations include c.1053_1058del in North Africans and c.2031-2041del in Iraqi-Jewish ethnicities (Fiore et al. 2012). Large deletions of the ITGB3 gene are rarely found in GT patients (Jallu et al. 2010). ITGB3 protein is the beta subunit making up the αIIbβ3 integrin complex, also known as CD41 and GpIIb/IIIa. Activation of the αIIbβ3 integrin complex allows platelets to bind fibrinogen and join to form platelet plugs at sites of vessel injury (Nurden et al, 2013).

Mutations in either ITGB3 or ITGA2B account for nearly all cases of GT. Clinical sensitivity for patients with GT symptoms (absence of platelet aggregation and αIIbβ3 expression) is >95% (Fiore et al. 2012). Analytical sensitivity for detection of causative mutations in both genes is >95% (Fiore et al. 2012) .

This test provides full coverage of all coding exons of the ITGB3 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).