Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis
Hereditary spherocytosis (HS), the most common cause of congenital hemolytic anemia, is caused by deficiency of the erythrocyte membrane proteins. Five causative genes (ANK1, SPTB, SPTA1, SLC4A1, and EPB42) have been identified. To date, molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes—17 in ANK1, 17 in SPTB and four in SLC4A1, suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a haploinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency (87.5% and 64.2%, respectively). Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based, especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency.
Keywordshereditary spherocytosis mutation ANK1 SPTB SLC4A1 whole-exome sequencing
Unable to display preview. Download preview PDF.
We thank all the individuals for their participation in this study. This work was supported by the National Key Research and Development Program of China (2016YFC0905100), the CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), the National Natural Science Foundation of China (NSFC) (81230015), the Beijing Municipal Science and Technology Commission (Z151100003915078), the Medical Science and Technology Research Projects of Henan Provincial Health Bureau (201601019) and the Scientific and Technological Projects of the Technology Bureau of Henan Provincial Technology (172102410010).
- Agarwal, A.M., Nussenzveig, R.H., Reading, N.S., Patel, J.L., Sangle, N., Salama, M.E., Prchal, J.T., Perkins, S.L., Yaish, H.M., and Christensen R.D. (2016). Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias. Br J Haematol 174, 806–814.CrossRefPubMedGoogle Scholar
- Bassères, D.S., Vicentim, D.L., Costa, F.F., Saad, S.T., and Hassoun, H. (1998). Beta-spectrin Promiss-ao: a translation initiation codon mutation of the beta-spectrin gene (ATG→GTG) associated with hereditary spherocytosis and spectrin deficiency in a Brazilian family. Blood 91, 368–369.PubMedGoogle Scholar
- Bouhassira, E.E., Schwartz, R.S., Yawata, Y., Ata, K., Kanzaki, A., Qiu, J. J., Nagel, R.L., and Rybicki, A.C. (1992). An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2NIPPON). Blood 79, 1846–1854.PubMedGoogle Scholar
- Bruce, L.J., Cope, D.L., Jones, G.K., Schofield, A.E., Burley, M., Povey, S., Unwin, R.J., Wrong, O., and Tanner, M.J. (1997). Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest 100, 1693–1707.CrossRefPubMedPubMedCentralGoogle Scholar
- Gallagher, P., and Lux, S. (2003). Disorders of the erythrocyte membrane. In: Nathan and Oski’s Hematology of Infancy and Childhood, D. Nathan, and S. Orkin, eds. (Philadelphia: Elsevier), pp. 560–684.Google Scholar
- Hassoun, H., Vassiliadis, J.N., Murray, J., Njolstad, P.R., Rogus, J.J., Ballas, S.K., Schaffer, F., Jarolim, P., Brabec, V., and Palek, J. (1997). Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency. Blood 90, 398–406.PubMedGoogle Scholar
- Ioannidis, N.M., Rothstein, J.H., Pejaver, V., Middha, S., McDonnell, S.K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., et al. (2016). REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99, 877–885.CrossRefPubMedPubMedCentralGoogle Scholar
- Jarolim, P., Palek, J., Rubin, H.L., Prchal, J.T., Korsgren, C., and Cohen, C. M. (1992). Band 3 Tuscaloosa: Pro327-Arg327 substitution in the cytoplasmic domain of erythrocyte band 3 protein associated with spherocytic hemolytic anemia and partial deficiency of protein 4.2. Blood 80, 523–529.PubMedGoogle Scholar
- Jarolim, P., Rubin, H.L., Brabec, V., Chrobak, L., Zolotarev, A.S., Alper, S. L., Brugnara, C., Wichterle, H., and Palek, J. (1995). Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood 85, 634–640.PubMedGoogle Scholar
- Lux, S.E., and Palek, J. (1995). Disorders of the red cell membrane. In: Blood: Principles and Practice of Hematology, R.I. Handin, S.E. Lux, and T.P. Stossel, eds. (Philadelphia: Lippincott), pp. 1701–1818.Google Scholar
- Rybicki, A.C., Qiu, J.J., Musto, S., Rosen, N.L., Nagel, R.L., and Schwartz, RS. (1993). Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40 glutamic acid→lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore). Blood 81, 2155–2165.PubMedGoogle Scholar