Identification of a novel hereditary spherocytosis gene mutation in a Chinese child with α-globin gene triplication

Abstract

Hereditary spherocytosis (HS) and thalassemia are both common hemolytic anemias, yet their pathogenesis is different. HS arises from erythrocyte membrane abnormalities, while thalassemia stems from defective hemoglobin synthesis. They both typically manifest in childhood, and diagnosis is often straightforward based on typical clinical manifestations and laboratory findings. Here, we report a unique case of co-occurring hematological disorders: HS and α-globin gene triplication, in a 2-year-old Chinese boy. The child had a history of longtime hemolytic disease and carried a novel heterozygous mutation which was not detected in either parent. The previously undescribed c.149-1G>A splicing mutation is speculated to affect pre-mRNA splicing. The coexistence of these conditions, along with a novel heterozygous mutation in the SPTB gene, highlights the complexity of genetic contributions to hemolytic anemias and underscores the importance of genetic testing in diagnosing and understanding these disorders.

Keywords

hereditary spherocytosis / α-globin gene triplication / hemolytic anemia / novel mutation / pediatrics

References

[1] Rets A , Clayton AL , Christensen RD , Agarwal AM . Molecular diagnostic update in hereditary hemolytic anemia and neonatal hyperbilirubinemia. Int J Lab Hematol 2019; 41(S1): 95–101

[2] He BJ , Liao L , Deng ZF , Tao YF , Xu YC , Lin FQ . Molecular genetic mechanisms of hereditary spherocytosis: current perspectives. Acta Haematol 2018; 139(1): 60–66

[3] Manciu S , Matei E , Trandafir B . Hereditary spherocytosis—diagnosis, surgical treatment and outcomes. A literature review. Chirurgia (Bucur) 2017; 112(2): 110–116

[4] Vercellati C , Marcello AP , Fattizzo B , Zaninoni A , Seresini A , Barcellini W , Bianchi P , Fermo E . Effect of primary lesions in cytoskeleton proteins on red cell membrane stability in patients with hereditary spherocytosis. Front Physiol 2022; 13: 949044

[5] Xie X , Gan J , Liu Z , Zhou Y , Yuan K , Chen Z , Chen S , Zhou R , Liu L , Huang X , Zhang Y , Liu Q , Zhang W , Huang J , Chen J . Prevalence and genetic analysis of triplicated α-globin gene in Ganzhou region using high-throughput sequencing. Front Genet 2023; 14: 1267892

[6] Chen Y , Xie T , Ma M , Yang J , Lv Y , Dong X . Case report: Identification of a novel triplication of alpha-globin gene by the third-generation sequencing: pedigree analysis and genetic diagnosis. Hematology 2023; 28(1): 2277571

[7] Gallagher PG . Diagnosis and management of rare congenital nonimmune hemolytic disease. Hematology 2015; 2015(1): 392–399

[8] Hamid M , Keikhaei B , Galehdari H , Saberi A , Sedaghat A , Shariati G , Mohammadi-Anaei M . Alpha-globin gene triplication and its effect in beta-thalassemia carrier, sickle cell trait, and healthy individual. eJHaem 2021; 2(3): 366–374

[9] Wu MY , Zhou JY , Li J , Li DZ . The frequency of α-globin gene triplication in a southern Chinese population. Indian J Hematol Blood Transfus 2016; 32(S1): 320–322

[10] Xi H , Liu Q , Xie DH , Zhou X , Tang WL , Tang G , Zeng CY , Wang Q , Nie XH , Peng JP , Gao XY , Wu HL , Zhang HQ , Qiu L , Feng ZH , Wang SY , Zhou SX , He J , Zhou SH , Zhou FQ , Zheng JQ , Wang SY , Chen SP , Zheng ZF , Ma XY , Fang JQ , Liang CB , Wang H . Epidemiological survey of hemoglobinopathies based on next-generation sequencing platform in Hunan Province, China. Biomed Environ Sci 2023; 36(2): 127–134

[11] Xie XM , Wu MY , Li DZ . Evidence of selection for the α-globin gene deletions and triplications in a southern Chinese population. Hemoglobin 2015; 39(6): 442–444

[12] Luo X , Zhang XM , Wu LS , Chen J , Chen Y . Prevalence and clinical phenotype of the triplicated α-globin genes and its ethnic and geographical distribution in Guizhou of China. BMC Med Genomics 2021; 14(1): 97

[13] Liang Q , Gu W , Chen P , Li Y , Liu Y , Tian M , Zhou Q , Qi H , Zhang Y , H J , Li Q , Tang L , Tang J , Teng Y , Zhou Y , Huang S , Lu Z , Xu M , Hou W , Huang T , Li Y , Li R , Hu L , Li S , Guo Q , Zhuo Z , Mou Y , Cram D , Wu L . A more universal approach to comprehensive analysis of thalassemia alleles (CATSA). J Mol Diagn 2021; 23(9): 1195–1204

[14] Liang Q , He J , Li Q , Zhou Y , Liu Y , Li Y , Tang L , Huang S , Li R , Zeng F , Mao A , Liu Y , Liang D , Wu L . Evaluating the clinical utility of a long-read sequencing-based approach in prenatal diagnosis of thalassemia. Clin Chem 2023; 69(3): 239–250

[15] Steinberg-Shemer O , Ulirsch JC , Noy-Lotan S , Krasnov T , Attias D , Dgany O , Laor R , Sankaran VG , Tamary H . Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia. Cold Spring Harb Mol Case Stud 2017; 3(6): a001941

[16] Haley K . Congenital hemolytic anemia. Med Clin North Am 2017; 101(2): 361–374

[17] Helmi N , Bashir M , Shireen A , Ahmed IM . Thalassemia review: features, dental considerations and management. Electron Physician 2017; 9(3): 4003–4008

[18] Farias MG . Advances in laboratory diagnosis of hereditary spherocytosis. Clin Chem Lab Med 2017; 55(7): 944–948

[19] Jamwal M , Sharma P , Das R . Laboratory approach to hemolytic anemia. Indian J Pediatr 2020; 87(1): 66–74

[20] Palmer L , Briggs C , McFadden S , Zini G , Burthem J , Rozenberg G , Proytcheva M , Machin SJ . ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. Int J Lab Hematol 2015; 37(3): 287–303

[21] Perrotta S , Gallagher PG , Mohandas N . Hereditary spherocytosis. Lancet 2008; 372(9647): 1411–1426

[22] He BJ , Liao L , Deng ZF , Tao YF , Xu YC , Lin FQ . Molecular genetic mechanisms of hereditary spherocytosis: current perspectives. Acta Haematologica 2018; 139(1): 60–66

[23] Bolton-Maggs PHB , Langer JC , Iolascon A , Tittensor P , King MJ . Guidelines for the diagnosis and management of hereditary spherocytosis—2011 update. Br J Haematol 2012; 156(1): 37–49

[24] Narla J , Mohandas N . Red cell membrane disorders. Int J Lab Hematol 2017; 39(S1): 47–52

[25] An X , Mohandas N . Disorders of red cell membrane. Br J Haematol 2008; 141(3): 367–375

[26] Wang R , Yang S , Xu M , Huang J , Liu H , Gu W , Zhang X . Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis. Sci China Life Sci 2018; 61(8): 947–953

[27] Ciepiela O . Old and new insights into the diagnosis of hereditary spherocytosis. Ann Transl Med 2018; 6(17): 339

[28] Li S , Guo P , Mi L , Chai X , Xi K , Liu T , Lu L , Li J . A novel SPTB mutation causes hereditary spherocytosis via loss-of-function of β-spectrin. Ann Hematol 2022; 101(4): 731–738

[29] Tole S , Dhir P , Pugi J , Drury LJ , Butchart S , Fantauzzi M , Langer JC , Baker JM , Blanchette VS , Kirby-Allen M , Carcao MD . Genotype-phenotype correlation in children with hereditary spherocytosis. Br J Haematol 2020; 191(3): 486–496

[30] Perrotta S , Della Ragione F , Rossi F , Avvisati RA , Di Pinto D , De Mieri G , Scianguetta S , Mancusi S , De Falco L , Marano V , Iolascon A . β-spectrin Bari: a truncated β-chain responsible for dominant hereditary spherocytosis. Haematologica 2009; 94(12): 1753–1757

[31] Liu H-X , Cartegni L , Zhang MQ , Krainer AR . A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genetics 2001; 27(1): 55–58

[32] Mort M , Ivanov D , Cooper DN , Chuzhanova NA . A meta-analysis of nonsense mutations causing human genetic disease. Human Mutation 2008; 29(8): 1037–1047

[33] Lindeboom RGH , Vermeulen M , Lehner B , Supek F . The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet 2019; 51(11): 1645–1651

[34] Oliveira MCLA , Fernandes RAF , Rodrigues CL , Ribeiro DA , Giovanardi MF , Viana MB . Clinical course of 63 children with hereditary spherocytosis: a retrospective study. Rev Bras Hematol Hemoter 2012; 34(1): 9–13

[35] Liu Y , Jin S , Li Y , Xu R , Pang W , Wang K , Wang Z , Chen Y . Treatment of asymptomatic gallstones in children with hereditary spherocytosis requiring splenectomy. J Pediatr Surg 2023; 58(4): 756–761

RIGHTS & PERMISSIONS

Higher Education Press