Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
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.
Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: omar.niss@cchmc.org.
Omar
O
Niss
Emory University School of Medicine, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Satheesh
S
Chonat
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Neha
N
Dagaonkar
Thalassemia and Genetic Center, Dubai, UAE.
Marya O
MO
Almansoori
SUNY Upstate Medical University, Syracuse, NY, USA.
Karol
K
Kerr
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Zora R
ZR
Rogers
Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Patrick T
PT
McGann
Emory University School of Medicine, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Maa-Ohui
MO
Quarmyne
College of Nursing, University of Cincinnati, Cincinnati, OH, USA.
Mary
M
Risinger
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Kejian
K
Zhang
Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Theodosia A
TA
Kalfa
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D004612:Elliptocytosis, Hereditary / Q000235:genetics*; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000648:ultrastructure; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008487:Medical History Taking; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D013049:Spectrin / Q000235:genetics
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C028841:erythrocyte membrane band 4.1 protein; D013049:Spectrin
Elliptocytosis; Hemolytic anemia; Mutation; Pyropoikilocytosis; Red blood cell membrane
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