Saes, Joline L.;
Simons, Annet;
de Munnik, Sonja A.;
Nijziel, Marten R.;
Blijlevens, Nicole M. A.;
Jongmans, Marjolijn C.;
van der Reijden, Bert A.;
Smit, Yolba;
Brons, Paul P.;
van Heerde, Waander L.;
Schols, Saskia E. M.
Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis
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Medientyp:
E-Artikel
Titel:
Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis
Beteiligte:
Saes, Joline L.;
Simons, Annet;
de Munnik, Sonja A.;
Nijziel, Marten R.;
Blijlevens, Nicole M. A.;
Jongmans, Marjolijn C.;
van der Reijden, Bert A.;
Smit, Yolba;
Brons, Paul P.;
van Heerde, Waander L.;
Schols, Saskia E. M.
Beschreibung:
<jats:sec><jats:title>Introduction</jats:title><jats:p>Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To describe the phenotype and genetic profile of patients with a bleeding tendency.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome‐wide analysis was performed if informed consent given.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in <jats:italic>MYH9</jats:italic> (two cases), <jats:italic>SLFN14</jats:italic>, <jats:italic>P2RY12 </jats:italic>and <jats:italic>GP9. </jats:italic>In addition, one case was considered solved due to combined carriership of <jats:italic>F7 </jats:italic>and <jats:italic>F13A1 </jats:italic>variants and one with combined carriership of <jats:italic>F2</jats:italic>, <jats:italic>F8 </jats:italic>and <jats:italic>VWF</jats:italic>, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: <jats:italic>GFI1B </jats:italic>and <jats:italic>VWF</jats:italic>. Eight patients were carriers of autosomal recessive disorders<jats:italic>.</jats:italic> Exome‐wide analysis was performed in 54 cases and identified three variants in candidate genes.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.</jats:p></jats:sec>