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A.T. Nurden and P. Nurden
gene panels is that some patients thought to have a mono- genic condition may in fact be seen to have digenic or oli- gogenic pathologies. The extent of bleeding or predisposi- tion to leukemia may crucially depend on gene variants that are different from those causing the primary disease. An early example is the ARID5B risk allele for leukemia in patients with ETV6-linked thrombocytopenias.156 A future step for modern technologies is to identify variants and gene modulators able to influence phenotype and bleed- ing - either by protecting against or by exaggerating the primary disease. This will be key to improving prognosis and prevention.
The use of cost-effective NGS procedures, with the con- tinued updating of gene panels, will require national net- works with links to high-performance bioinformatics cen- ters able to best analyze the data, perform variant filtering as well as the quality control of the sequencing procedures. As we have proposed elsewhere, this will be best done for Europe with a consensus132 in which the European
Hematology Association can be a leader providing guide- lines, as is already the case with its comprehensive roadmap for hematology research.157 Early recognition of a germline mutation facilitates appropriate treatment, better monitoring for disease progression, proper donor selection for HSC transplantation (family members must also be tested to ensure that they do not carry the mutation), as well as optimal genetic counseling of the affected patients and their family. Quite clearly for many patients the asso- ciated pathologies are clinically more serious than the bleeding risk and for some there is an obvious age-depen- dence. Improving the quality of life of patients and, at the same time, avoiding their stigmatization requires compre- hensive ethical considerations.158 It is crucial to decide how to provide delicate genetic information concerning a poten- tial risk for leukemia or cancer, especially when potentially causal variants are found in young children, or how to deal with the coincidental identification of gene defects likely to predict other major illnesses.
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