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A case report of congenital erythropoietic anemia II in China with a novel mutation

  • Hong Zhang
  • Wuqing WanEmail author
  • Xiaoyan Liu
  • Chuan Wen
  • Ying Liu
  • Senlin Luo
  • Xiao Sun
  • Shizhe Liu
Open Access
Letter to the Editor

Dear Editor,

Congenital erythropoietic anemias (CDAs) are a group of rare inherited diseases [1]. So far, the CDAs are mainly divided into four types (type I to type IV), and the CDA type II is the most common type. It is caused by a mutation in the SEC23B gene. To date, 67 causative mutations in the SEC23B gene have been described [2, 3, 4, 5] (the complete mutational spectrum of SEC23B is shown in Table 1).
Table 1

Mutational spectrum of SEC23B

Exon

Nucleotide change

AA change

Missense mutations

 2

c.40C > T

R14W

 2

c.53G > A

R18H

 2

c.74C > A

P25H

 2

c.197G > A

C66Y

 4

c.325G > A

E109K

 5

c.494G > A

G165D

 7

c.716A > G

D239G

 8

c.938G > A

R313H

 8

c.953T > C

I318T

 9

c.1043A > C

D348A

 10

c.1157A > G

Q386R

 11

c.1254T > G

I418M

 11

c.1307C > T

S436L

 11

c.1352G > T

C451F

 12

c.1385A > G

Y462C

 12

c.1445A > G

Q482R

 13

c.1453A > G

T485A

 13

c.1467C > G

H489Q

 13

c.1489C > T

R497C

 13

c.1508G > A

R503Q

 14

c.1571C > T

A524V

 14

c.1588C > T

R530W

 14

c.1589G > A

R530Q

 14

c.1654C > T

L552F

 15

c.1685A > G

Y562C

 15

c.1727T > C

F576S

 15

c.1733T > C

L578P

 15

c.1735T > A

Y579N

 16

c.1808C > T

S603L

 16

c.1832G > C

R611P

 16

c.1858A > G

M620V

 16

c.1859T > C

M620T

 17

c.1910T > G

V637G

 17

c.1949T > C

L650S

 17

c.1968T > G

F656L

 18

c.2101C > T

R701C

 17

c.2108C > T

P703L

 18

c.2129C > T

T710M

 19

c.2166A > C

K723Q

 19

c.2180C > T

S727F

 20

c.2270A > C

H757P

Nonsense mutations

 2

c.71G > A

W24X

 3

c.235C > T

R79X

 5

c.367C > T

R123X

 5

c.568C > T

R190X

 6

c.640C > T

Q214X

 6

c.649C > T

R217X

 7

c.790C > T

R264X

 8

c.970C > T

R324X

 9

c.1015C > T

R339X

 10

c.1201C > T

R401X

 14

c.1603C > T

R535X

 14

c.1648C > T

R550X

 14

c.1660C < T

R554X

Splicing mutations

 2–3

c.221 + 31A > G

 

 3–4

c.279 + 3A > G

 

 6

c.689 + 1G > A

 

 9–10

c.1109 + 1G > A

 

 9–10

c.1109 + 5G > A

 

 18–19

c.2149-2A > G

 

Frameshift mutations

 3

c.222-817_366 + 4242del

 

 5

c.387(delG)

 

 5

c.428_428delAinsCG

 

 9

c.1063(delG)

 

 16

c.1821delT

 

 17

c.1962-64(delT)

 

 19

c.2150(delC)

 

Small deletion

 16

c.1857_1859delCAT

 

We report a patient with typical clinical manifestations and laboratory findings, a 6-year-old girl who had suffered jaundice at the age of 6 months with low hemoglobin levels at 80 g/L. Her hemoglobin concentration fluctuated between 80 and 100 g/L, and the severe hemoglobin lows were complicated with jaundice, which was not treated. There was no clear diagnosis even after comprehensive examinations. She tended to catch colds easily. Her parents and a younger brother were all healthy. Upon physical examination, the proband displayed anemic facies and yellowish discoloration of the mucous membrane and skin. Abdominal examination showed hepatomegaly and splenomegaly.

Laboratory investigations showed a hemoglobin level of 78 g/L. Reticulocyte count was 0.069 × 10^12/L, and reticulocyte ratio was 3.16%. Total bilirubin was 53.9 μmol/L (normal, 0–21), of which 42.7 μmol/L was indirect (normal, 0–19). G6PD deficiency was not found. Red blood cell folate and hemoglobin electrophoresis gave results within normal limits. Serum vitamin B12 was 736 pmol/L (normal, 133–675). Serum iron, ferritin, and transferrin were all within normal limits. Erythrocyte osmotic fragility test was normal. Acidified glycerol hemolysis test and Coombs test were negative. Light microscope observation of a bone marrow smear revealed hyperplasia and binucleated late erythroblasts (Fig. 1a).
Fig. 1

a A binucleated late erythroblast on bone marrow smear. b Heterozygous mutation (c.T1859C) of the proband and her father. c Heterozygous mutation (c. C1571T) of the proband and her mother

Genetic testing of the proband, her little brother, and her parents performed at Shanghai Xin Peijing Medical Laboratory showed two heterozygous changes in the SEC23B gene of chromosome 20, which were heterozygote c.C1571T: p.A524V (on exon 14) and heterozygote c.T1859C: p.M620T (on exon 16). The proband was a compound heterozygote with mutation c.C1571T from her mother and c.T1859C from her father. Her little brother inherited the mutation from their mother (Fig. 1b, c).

In this case, sequencing analysis of CDA-related genes revealed that there were two mutations of SEC23B gene in this family: c. C1571T: p.A524V (on exon 14) and c.T1859C: p.M620T (on exon 16). The proband was a compound heterozygote with mutation c.C1571T from her mother and c.T1859C from her father. Since she was the only patient in this family, the illness of the proband was inferred to have been caused by a compound heterozygous mutation and not by a single mutation. The mutation c. C1571T has been reported [2]. A search of PubMed indicated that the mutation c.T1859C has not yet been reported. Here, we attempted to prove that it was a causative mutation. First, this mutation is located in the gelsolin domain of SEC23B protein, which has an extremely important function. The sequences around this domain are highly conserved among multiple species shown using the Protein BLAST tool. We used the PolyPhen tool to evaluate the possible effects of this mutation. The result was “probably damaging.” Russo [4] reported a CDA II patient whose gene mutation was c.A1858G (on exon 16), adjacent to the mutation site of the proband. Both these mutations resulted in a change in the amino acid at position 620. We believe that mutation c.T1859C is a causative and novel mutation of CDA II.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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ESM 1 (RAR 2181 kb)

References

  1. 1.
    Lolascon A, D’Agostaro G, Perrotta S et al (1996) Congenital dyserythropoietic anemia type II: molecular basis and clinical aspects.[J]. Haematologica 81(6):543Google Scholar
  2. 2.
    Lolascon A, Esposito MR, Russo R (2012) Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach.[J]. Haematologica 97(12):1786–1794CrossRefGoogle Scholar
  3. 3.
    Lolascon A, Russo R, Esposito MR et al (2010) Molecular analysis of 42 patients with congenital dyserythropoietic anemia type II: new mutations in the SEC23B gene and a search for a genotype-phenotype relationship.[J]. Haematologica 95(5):708–715CrossRefGoogle Scholar
  4. 4.
    Russo R, Esposito MR, Asci R, Gambale A, Perrotta S, Ramenghi U, Forni GL, Uygun V, Delaunay J, Iolascon A (2010) Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel variants in SEC23B gene.[J]. Am J Hematol 85(12):915–920CrossRefGoogle Scholar
  5. 5.
    Wang Y, Ru Y, Liu G et al (2017) Identification of CDAN1, C15ORF41 and SEC23B mutations in Chinese patients affected by congenital dyserythropoietic anemia.[J]. Gene 640:73CrossRefGoogle Scholar

Copyright information

© The Author(s) 2019

OpenAccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Hong Zhang
    • 1
  • Wuqing Wan
    • 1
    Email author
  • Xiaoyan Liu
    • 1
  • Chuan Wen
    • 1
  • Ying Liu
    • 1
  • Senlin Luo
    • 1
  • Xiao Sun
    • 1
  • Shizhe Liu
    • 1
  1. 1.Department of Pediatrics, the Second Xiangya HospitalCentral South UniversityChangshaChina

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