Two Novel GATA1 Mutations in Transient Abnormal Myelopoiesis of Thai Neonates with Down Syndrome

Abstract

Children with Down syndrome (DS) are 150 times more likely to develop acute myeloid leukemia (ML-DS), compared with those without. One risk factor is transient abnormal myelopoiesis (TAM). Somatic truncating GATA1 mutations are found in most TAM patients and are markers for future ML-DS. We identified two novel frameshift mutations in our seven newborns with DS and TAM: a heterozygous mutation of 17 nucleotide duplication (c.154_170 dup) and a heterozygous 9-nucleotide deletion combined with a 2-nucleotide insertion (c.150_158delins CT). Both mutations introduced a truncated GATA1 protein. Thus, neonates with DS and TAM require frequent ML-DS monitoring.

Keywords

transient abnormal myelopoiesis - Down syndrome - GATA1 mutation

Authors' Contributions

K.C., C.N., and K.P. performed genetic testing and wrote the manuscript; T.K. supervised genetic testing; P.C. and O.P. reviewed clinical data and wrote manuscript; S.P., S.K., W.T., P.S., W.S., and T.P. were attending physicians; P.S. was an attending physician, supervised, reviewed clinical data, and edited manuscript; K.R. designed the study, supervised genetic tests, wrote and edited manuscript.

• References

• 1 Zipursky A. Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 2003; 120 (06) 930-938
• 2 Mateos MK, Barbaric D, Byatt SA, Sutton R, Marshall GM. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl Pediatr 2015; 4 (02) 76-92
• 3 Gamis AS, Alonzo TA, Gerbing RB. , et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 2011; 118 (26) 6752-6759 , quiz 6996
• 4 Roberts I, Alford K, Hall G. , et al; Oxford-Imperial Down Syndrome Cohort Study Group. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 2013; 122 (24) 3908-3917
• 5 Vardiman JW, Thiele J, Arber DA. , et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114 (05) 937-951
• 6 Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I. Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. Curr Hematol Malig Rep 2016; 11 (05) 333-341
• 7 Massey GV, Zipursky A, Chang MN. , et al; Children's Oncology Group (COG). A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 2006; 107 (12) 4606-4613
• 8 Roy A, Cowan G, Mead AJ. , et al. Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci U S A 2012; 109 (43) 17579-17584
• 9 Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 2000; 355 (9199): 165-169
• 10 Klusmann JH, Creutzig U, Zimmermann M. , et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008; 111 (06) 2991-2998
• 11 Kanezaki R, Toki T, Terui K. , et al. Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Blood 2010; 116 (22) 4631-4638
• 12 Malinge S, Izraeli S, Crispino JD. Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 2009; 113 (12) 2619-2628
• 13 Wechsler J, Greene M, McDevitt MA. , et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32 (01) 148-152
• 14 Bombery M, Vergilio JA. Transient abnormal myelopoiesis in neonates: GATA get the diagnosis. Arch Pathol Lab Med 2014; 138 (10) 1302-1306
• 15 Sankaran VG, Ghazvinian R, Do R. , et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest 2012; 122 (07) 2439-2443
• 16 Nichols KE, Crispino JD, Poncz M. , et al. Familial dyserythropoieticanaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 2000; 24 (03) 266-270
• 17 Alford KA, Reinhardt K, Garnett C. , et al; International Myeloid Leukemia-Down Syndrome Study Group. Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 2011; 118 (08) 2222-2238
• 18 Tunstall O, Bhatnagar N, James B. , et al; British Society for Haematology. Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome. Br J Haematol 2018; 182 (02) 200-211
• 19 Lum SH, Choong SS, Krishnan S, Mohamed Z, Ariffin H. GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder. Singapore Med J 2016; 57 (06) 320-324
• 20 Harigae H, Xu G, Sugawara T, Ishikawa I, Toki T, Ito E. The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. Blood 2004; 103 (08) 3242-3243
• 21 Rohlin A, Wernersson J, Engwall Y, Wiklund L, Björk J, Nordling M. Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat 2009; 30 (06) 1012-1020
• 22 Schifferli A, Hitzler J, Bartholdi D. , et al. Transient myeloproliferative disorder in neonates without Down syndrome: case report and review. Eur J Haematol 2015; 94 (05) 456-462