Characterization of hereditary red blood cell membranopathies using combined targeted next-generation sequencing and osm
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ORIGINAL ARTICLE
Characterization of hereditary red blood cell membranopathies using combined targeted next‑generation sequencing and osmotic gradient ektacytometry Joan‑Lluis Vives‑Corrons1,3 · Elena Krishnevskaya1 · Ines Hernandez Rodriguez2 · Agueda Ancochea2 Received: 17 April 2020 / Revised: 20 August 2020 / Accepted: 24 September 2020 © Japanese Society of Hematology 2020
Abstract Hereditary red blood cell (RBC) membranopathies are characterized by mutations in genes encoding skeletal proteins that alter the membrane complex structure. Hereditary spherocytosis (HS) is the most common inherited RBC membranopathy leading to hereditary hemolytic anemia with a worldwide distribution and an estimated prevalence, in Europe, of about 1:2000 individuals. The recent availability of targeted next generation sequencing (t-NGS) and its combination with RBC deformability measured with a laser-assisted optical rotational ektacytometer (LoRRca) has demonstrated to be the most powerful contribution to lower the percentage of hereditary hemolytic anemia undiagnosed cases. In order to know the kind and frequency of RBC membrane mutations in our geographical area (Catalonia) and to better understand their pathophysiology, 42 unrelated, non-transfusion-dependent (NTD) patients with hereditary hemolytic anemia have been studied by combining t-NGS and LoRRca. The osmoscan module of LoRRca provides three rheological profiles that reflect the maximal deformability (EImax), osmotic fragility (Omin), and hydration state (Ohyper) of RBCs and contribute to a better understanding of the contribution RBC rheology to the severity of anemia. From the 42 patients studied, 37 were suspected to be a RBC membrane defect due to phenotypic characteristics and abnormal RBC morphology and, from these, in 31 patients (83.8% of cases) the mutation was identified by t-NGS. No definite diagnosis was achieved in 11 patients (26.2% of cases), including 6 out of 37 cases, with suspected membranopathy, and 5 with unclassifiable HHA. In all these undiagnosed patients, the existence of hemoglobinopathy and/or enzymopathy was ruled out by conventional methods.
Introduction Rare anemias (RA) are, in more than 80% of cases, genetic disorders caused by mutations in the genes controlling erythropoiesis and/or red blood cell (RBC) structural components [1]. Abnormalities of RBC structural components constitute a cause of hereditary hemolytic anemia (HHA) and are classified into three categories: hemoglobinopathies, * Joan‑Lluis Vives‑Corrons [email protected] 1
Red Blood Cells and Haematopoietic Disorders (Rare Anaemias Unit), Josep Carreras Institute for Leukaemia Research (IJC), Badalona (Barcelona), Spain
2
Haematology Department, Hospital Universitari Germans Trias i Pujol-ICO. Autonomous University of Barcelona, Badalona (Barcelona), Spain
3
Medicine Department, University of Barcelona, Catalonia, Spain
membranopathies and enzymopathies. Hemoglobinopathies and enzymopathies are, in general, easily diagnosed by conventional laboratory test
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