Page 50 - Haematologica April 2020

J. Perez Botero et al.
selors can support clinicians by providing pre- and post- test genetic counseling to patients and families in the clin- ical setting, and can also aid clinicians in test selection and ordering, and in navigating the process of obtaining insur- ance approval for payment. This is particularly relevant in healthcare systems with multiple payers and multiple testing options. As commercial laboratories offer different services, the clinician should be familiar with the testing methodology and any related limitations.
Given the highly specific phenotype of GT, after platelet aggregation studies and flow cytometry have been performed, genetic testing of ITGA2B and ITGB3 only, as opposed to a panel approach that includes multi- ple other genes, is appropriate (Figure 2). Sequence analy- sis will detect the vast majority of pathogenic variants; when sequencing fails to identify both pathogenic vari- ants in a patient with GT, specific deletion/duplication analysis should be considered.
Targeted variant analysis, which is expected to save time and money, can be performed in populations with a known pathogenic variant(s) and high rates of consan- guinity; however, with this approach, a second GT vari- ant in the same gene may go undetected.27 Targeted vari- ant analysis is best adopted when the pathogenic variant in each allele has been identified in an affected individual.
Variant curation and initiatives for standardization
In recent years, several initiatives have been taken to provide guidance for the analysis and reporting of molec- ular findings, specifically in terms of variant classification when attributing pathogenicity. In the United States, the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) published guidelines in 2015 for the interpretation of vari- ants, providing a framework for clinical molecular labora- tories.14 While these guidelines have been extremely use- ful in the laboratory practice, they are not disease specif- ic, and significant challenges remain when applied to par- ticular disease states. In an effort to address this limita- tion, and to improve the quality, consistency and access to clinical genomic data, the National Institutes of Health (NIH) funded resource ClinGen is leading initiatives including the formation of Variant Curation Expert Panels (VCEP). Each VCEP consists of a cross-institutional team of experts from complementary specialties, the fields of
hematology and genetics, from academia and industry, working collaboratively with the goal of adapting the ACMG criteria for specific genes or disorders.28
The Platelet Disorder Variant Curation Expert Panel (VCEP) created in 2018 and supported by the American Society of Hematology, is composed of 28 international scientists and clinicians with expertise in hematology and genetics, and has been working on the adaptation of the ACMG rules for the interpretation of variants in ITGA2B and ITGB3. The goals of this collaboration are to produce high quality variant curation data that are publicly avail- able and create a framework for GT variant curation that allows others to systematically and comprehensively approach genetic data encountered in clinical and research settings.
The VCEP has used estimates of prevalence and popu- lation data to define criteria for allele frequency that ulti- mately serve as standalone, strong or supporting evidence to classify variants as benign, which is a difficult task in rare disorders for which the precise incidence data are not available. Clinical expertise was key in defining the phe- notype from a clinical presentation (bleeding phenotype) and clinical laboratory standpoint (platelet aggregation and glycoprotein expression studies), which together are unique to GT. Knowledge of the molecular biology of the disorder allowed for elimination of codes that do not apply for this disease state and points for segregation analysis were modified taking into account the disease inheritance, low frequency and specific clinical pheno- type. Special consideration was given to defining the type of assays that provide quality functional evidence in dif- ferent in vivo and in vitro systems and models. The disease specified rules were tested in a subset of variants which will be uploaded to ClinVar with a 3-star rating. Variants assessed by approved ClinGen VCEP also receive a US Food and Drug Administration (FDA) approval label. A detailed description of the rule specifications for GT will soon be available to the public.
Management
Patients with GT benefit from being managed at a center with expertise in inherited bleeding disorders, with access to staff who are able to provide recommendations and
Table 1. Measures and medications available for the management of bleeding in Glanzmann thrombasthenia (GT). Treatment Clinical situation
Local measures Mild bleeding at a visible/compressible site • Compression
• Gauze or sponge dipped in antifibrinolytic or topical thrombin
• Nasal packing
• Gel foam soaked in antifibrinolytic or topical thrombin
Antifibrinolytics
• Tranexamic acid • Aminocaproic acid
rFVIIa
Platelet transfusion*
As monotherapy in mild bleeding
As combination therapy in moderate and severe bleeding Moderate to severe bleeding
Alone for minor surgical procedures or in combination with antifibrinolytics and/or platelet transfusions for major procedures and severe or life-threatening bleeding
In combination with rFVIIa and/or antifibrinolytics in severe bleeding and major surgical procedures
rFVIIa: recombinant activated coagulation factor VII. *Risk of lack of efficacy in the setting of alloimmunization.
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