Abstract
Hereditary spherocytosis (HS) is an inherited heterogeneous hemolytic anemia, characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, and the clinical manifestation ranges from asymptomatic to severely anemic, and transfusion-dependent patients. Mutations in at least five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB) have been identified so far, and mutations of ANK1 gene are responsible for the majority of all HS cases. In this study, targeted next generation sequencing (NGS) was applied to identify a novel de novo ANK1 c.4276C>T (p.R1426*) nonsense mutation in a Chinese family with a patient of HS who was diagnosed clinically with only 10% spherical-shaped erythrocytes in the peripheral blood and received splenectomy. Sanger sequencing further confirmed that only the patient carried heterozygous ANK1 c.4276C>T nonsense mutation, while none of his parents or his young brother carried this mutation. Moreover, consistent with the genetic findings, the anemia was ameliorated after splenectomy. RBCs increased from 2.74 × 1012/L pre-surgery to 4.76 × 1012/L one month post-surgery, and hemoglobin increased from 66g/L to 126g/L respectively. This is the first report of ANK1 c.4276C>T (p.R1426*) heterozygous nonsense mutation responsible for HS. Our results also demonstrate that targeted NGS may provide a powerful approach for rapid genetic test of HS.
Highlights
Hereditary spherocytosis (HS) is the most frequent form of inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, hemolysis, splenomegaly, jaundice, and gallstones [1]
Consistent with the genetic findings, the anemia was ameliorated after splenectomy
The changes of RBC and Hemoglobin of the patient with HS pre/post-surgery was recorded in Table 1, and the anemia was ameliorated after splenectomy
Summary
Hereditary spherocytosis (HS) is the most frequent form of inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, hemolysis, splenomegaly, jaundice, and gallstones [1]. Mutations in at least five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB), encoding ankyrin, protein 4.2, band 3 protein, α-spectrin, and β-spectrin respectively, are associated with HS. The majority of HS cases is associated with autosomal dominant (AD) pattern, autosomal recessive (AR) inheritance has been described. Mutations in ANK1 (mainly nonsense and frame shift mutations) are responsible for about 75% of cases of HS www.impactjournals.com/oncotarget in humans, followed by mutations in SLC4A1 and SPTB genes [3, 4]. Erythroid ankyrin is a major protein in RBCs involved in the linkage of transmembrane proteins and the cell membrane skeleton via spectrin, band 4.2 protein, band 3 protein, and ankyrin deficiency results in reduced incorporation of spectrin [7]. 59 distinct ANK1 mutations have been reported in human HS in HGMD database 59 distinct ANK1 mutations have been reported in human HS in HGMD database (www. hgmd.cf.ac.uk), including deletion, frameshift, nonsense, or missense mutations
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