Characterization of causal variants associated with hereditary thrombocytopenias

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F19%3A00072114" target="_blank" >RIV/65269705:_____/19:00072114 - isvavai.cz</a>

Result on the web

<a href="https://eventpilotadmin.com/doc/clients/ASHG/ASHG19/library/pdf/abstract_1922425.pdf?display" target="_blank" >https://eventpilotadmin.com/doc/clients/ASHG/ASHG19/library/pdf/abstract_1922425.pdf?display</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Characterization of causal variants associated with hereditary thrombocytopenias

Original language description

Inherited thrombocytopenias (IT) are a heterogeneous group of 33 different forms of monogenic disorders caused by molecular defects affecting at least 40 genes. Pathogenic variants in these genes usually lead to the disruption of megakaryopoietic and thrombopoietic processes and present as the thrombocytopenia phenotype (low platelet count, blood-examination). However, patients are occasionally misdiagnosed with the immune thrombocytopenia and unsuccessfully treated with steroid therapy and splenectomy. In some patients, accurate diagnosis of IT can only be established based on the results of molecular genetic testing. In our patient cohort, we have identified novel variants in three IT families. First, a rare variant in a proband with Wiskott-Aldrich syndrome who was originally misdiagnosed as Bernard-Soulier syndrome. Second, the both family members carried a variant for TRPM7-related trombocytopenia and one of them had hematooncological disease in their medical history. We detected in the third family rare variants of autosomal recessive Glanzmann thrombasthenia which was caused by mutations in the ITGA2B gene. Germline DNA analysis was performed on all available samples and somatic DNA analysis was done for the oncological patient. Sequencing libraries were prepared according to the SeqCap EZ Human Exome Probes v3 protocol and sequencing was performed on NextSeq500. Within each family, the obtained variants were compared between the individuals with thrombocytopenia phenotype and their disease-free relatives. Using whole exome sequencing (WES), we characterized an unique variant segregating with thrombocytopenia phenotype for each of the three families: WAS: NM_000377: exon 10:c.998G&gt;C:p.Gly333Ala, TRPM7: NM_017672: exon4:c.223A&gt;G:p.I75V, and ITGA2B: NM_000419: exon29:c.2965G&gt;A:p.A989T; exon29:c.2944G&gt;A:p.V982M. In silico analysis revealed a structural defect of amino acid changes found in the protein structures, indicating that all of the variants are We identified a causal variant for each of the families analysed. These results helped the clinicians determine the correct diagnosis to patients. Besides that, accurate diagnosis of IT allow clinicians to conduct further examinations if the identified variant poses additional risk to the carrier, i.e., a higher risk of oncological disorders.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30205 - Hematology

Project

<a href="/en/project/NV16-29447A" target="_blank" >NV16-29447A: Searching for mutations predisposing to familial hematologic and oncologic diseases</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů