Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis

• Type of Material: Article
• Authors: Omar Niss, Cincinnati Children's Hospital Medical Center; Satheesh Chonat, Emory University; Neha Dagaonkar, Cincinnati Children's Hospital Medical Center; Marya O. Almansoori, Thalassemia and Genetic Center; Karol Kerr, SUNY Upstate Medical University; Zora R. Rogers, University of Texas Southwestern Medical Center; Patrick T. McGann, Cincinnati Children's Hospital Medical Center; Maa-Ohui Quarmyne, Emory University; Mary Risinger, University of Cincinnati; Kejian Zhang, Cincinnati Children's Hospital Medical Center; Theodosia A. Kalfa, Cincinnati Children's Hospital Medical Center
• Language: English
• Date: 2016-10
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bcmd.2016.07.003
• Title of Journal or Parent Work: Blood Cells, Molecules and Diseases
• ISSN: 1079-9796
• Volume: 61
• Start Page: 4
• End Page: 9
• Grant/Funding Information: The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 1UL1TR001425-01.
• Keywords: Hematology; Science & Technology; Hemolytic anemia; HETERODIMER; Elliptocytosis; GENE; Mutation; SPHEROCYTOSIS; DISORDERS; BETA-SPECTRIN; RED-CELL MEMBRANE; MUTATIONS; Red blood cell membrane; Life Sciences & Biomedicine; SELF-ASSOCIATION SITE; Pyropoikilocytosis
• Research Categories: Biology, Genetics

Abstract

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival. The clinical diagnosis of HE and HPP relies on identifying characteristic RBC morphology on peripheral blood smear and specific membrane biomechanical properties using osmotic gradient ektacytometry. However, this phenotypic diagnosis may not be readily available in patients requiring frequent transfusions, and does not predict disease course or severity. Using Next-Generation sequencing, we identified the causative genetic mutations in fifteen patients with clinically suspected HE or HPP and correlated the identified mutations with the clinical phenotype and ektacytometry profile. In addition to identifying three novel mutations, gene sequencing confirmed and, when the RBC morphology was not evaluable, identified the diagnosis. Moreover, genotypic differences justified the phenotypic differences within families with HE/HPP.