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Inherited Coagulopathies Study by Massive Sequencing (NGS) Experience of a Diagnostic Portuguese Center

1Centro Hospitalar e Universitário de Coimbra, Molecular Hematology Laboratory, Clinical Hematology, Coimbra, Portugal, 2Centro Hospitalar Universitário Lisboa Norte, Hospital Santa Maria, Reference Centre of Congenital Coagulopathies, Lisboa, Portugal, 3Centro Hospitalar e Universitário de Coimbra, Reference Centre of Congenital Coagulopathies, Coimbra, Portugal, 4Centro Hospitalar Universitário de S. João, Reference Centre of Congenital Coagulopathies, Porto, Portugal, 5Hospital de Braga, Reference Centre of Congenital Coagulopathies, Braga, Portugal, 6Centro Hospitalar Universitário do Algarve, Hospital de Faro, Hematology Service, Faro, Portugal, 7Centro Hospitalar Lisboa Central - Hospital D. Estefânia, Hematology Service, Lisboa, Portugal, 8Centro Hospitalar Tondela-Viseu, Reference Centre of Congenital Coagulopathies, Viseu, Portugal

Abstract Number: PB0690

Meeting: ISTH 2020 Congress

Theme: Diagnostics and OMICs » Laboratory Diagnostics

Background: Next-generation sequencing (NGS) with targeted gene panels introduced substantial benefits in the clinical practice regarding definitive diagnosis in certain haematological diseases in which the candidate gene is not obvious. It changed study algorithms in diagnostic centres and contributes to a broader view of the molecular causes of diseases, identifying genetic heterogeneity and allowing a better genotype/phenotype correlation.

Aims: To improve diagnostic capacity with NGS workflow using a panel of Thrombosis and Haemostasis (TH) which includes 43 genes for the diagnosis of Inherited Bleeding Diseases, Thrombosis and suspected Platelet disorders (IBD, T and PD).

Methods: 496 patients were studied (mean age 34,5 years (1M-78); 257F:239M, since may/2017, from several central hospitals with clinical data of IBD (n=311), T (n=133) and PD (n=52), for elucidation of molecular diagnosis with the panel PTH/NGS IONS5. Study algorithm includes, in severe haemophilia A, initial exclusion of F8 inversions and posterior detection of deletions/duplications by MLPA.

Results: In 300/496 patients were identified variants that justified the phenotype and were consistent with functional studies. A total of 146 different pathogenic/likely pathogenic/UVS variants in 28/43 genes were found, 42 not previously described. In 226/311 (73%) IBD patients (haemophilia, VWD, fibrinogen and other factor deficiencies) variants were detected in F5,F7,F8,F9,F10,F11,F12,F13A1,LMAN1, FGA,FGB,FGG,GGCX,VWF; In 29/52 (56%) PD patients (thrombocytopenias and functional platelet disorders), variants were identified in GP1BA,GP6,PLAU,TBXA2R,ITGA2B,ITGB3,NBEAL2,ANKRD26 and TUBB1; only in 45/133 (34%) patients with thrombosis, variants were identified in PROC,PROS1,F3,FGG,PLG and SERPINC1. Double and compound heterozygous has explained different intra/interfamilial patient’s phenotypes.

Conclusions: Sensitivity in mutation detection was different between the 3 groups, being the thrombosis group the one revealing lower diagnostic efficacy. These data show the need of exome study in some patients. NGS reveals to be a valuable tool in our clinical practice and provides more accurate diagnosis helping to determine the most effective treatment in these complex diseases.

To cite this abstract in AMA style:

Martinho P, Silva Pinto C, Oliveira C, Rodrigues MF, Salvado R, Carvalho M, Calheiros M, Caetano G, Araújo LF, Azevedo J, Kjollerstrom P, Costa M, Fidalgo T, Ribeiro ML. Inherited Coagulopathies Study by Massive Sequencing (NGS) Experience of a Diagnostic Portuguese Center [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/inherited-coagulopathies-study-by-massive-sequencing-ngs-experience-of-a-diagnostic-portuguese-center/. Accessed September 22, 2023.

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