Glanzmann thrombasthenia: Genetic basis and clinical correlates

Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by th

Glanzmann thrombasthenia: genetic basis and clinical correlates

Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the ITGA2B and ITGB3 genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular studies confirm the diagnosis. Management of bleeding is based on a combination of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complications. In addition, pregnant patients pose unique management challenges. This review highlights clinical and molecular aspects in the approach to patients with GT, with particular emphasis on the significance of multidisciplinary care.status: publishe

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/ population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.Fil: Ross, Justyne E.. University of North Carolina; Estados UnidosFil: Zhang, Bing M.. University of Stanford; Estados UnidosFil: Lee, Kristy. University of North Carolina; Estados UnidosFil: Mohan, Shruthi. University of North Carolina; Estados UnidosFil: Branchford, Brian R.. Versiti Blood Center of Wisconsin; Estados UnidosFil: Bray, Paul. University of Utah. School of Medicine; Estados UnidosFil: Dugan, Stefanie N.. Versiti Blood Center of Wisconsin; Estados UnidosFil: Freson, Kathleen. Katholikie Universiteit Leuven; BélgicaFil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Kahr, Walter H. A.. University Of Toronto. Hospital For Sick Children; Canadá. University of Toronto; CanadáFil: Lambert, Michele P.. The Children's Hospital Of Philadelphia; Estados Unidos. University of Pennsylvania; Estados UnidosFil: Luchtman Jones, Lori. Cincinnati Children's Hospital Medical Center; Estados Unidos. University of Cincinnati; Estados UnidosFil: Luo, Minjie. The Children's Hospital Of Philadelphia; Estados UnidosFil: Botero, Juliana Perez. Medical College Of Wisconsin; Estados UnidosFil: Rondina, Matthew T.. State University of Utah; Estados Unidos. George E. Wahlen VA Medical Center; Estados UnidosFil: Ryan, Gabriella. American Society Of Hematology; Estados UnidosFil: Westbury, Sarah. University of Bristol; Reino UnidoFil: Bergmeier, Wolfgang. University of North Carolina; Estados UnidosFil: Di Paola, Jorge. Washington University in St. Louis; Estados Unido