title: GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.
abstract: Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College London, London, United Kingdom;
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
authors.forename: Kate
authors.initials: K
authors.lastname: Alford
authors.forename: Georgina
authors.initials: G
authors.lastname: Hall
authors.forename: Gaetan
authors.initials: G
authors.lastname: Juban
authors.forename: Helen
authors.initials: H
authors.lastname: Richmond
authors.forename: Alice
authors.initials: A
authors.lastname: Norton
authors.forename: Grant
authors.initials: G
authors.lastname: Vallance
authors.forename: Kelly
authors.initials: K
authors.lastname: Perkins
authors.forename: Emanuele
authors.initials: E
authors.lastname: Marchi
authors.forename: Simon
authors.initials: S
authors.lastname: McGowan
authors.forename: Anindita
authors.initials: A
authors.lastname: Roy
authors.forename: Gillian
authors.initials: G
authors.lastname: Cowan
authors.forename: Mark
authors.initials: M
authors.lastname: Anthony
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.forename: John
authors.initials: J
authors.lastname: Ho
authors.forename: Sabita
authors.initials: S
authors.lastname: Uthaya
authors.forename: Anna
authors.initials: A
authors.lastname: Curley
authors.forename: Shree Vishna
authors.initials: SV
authors.lastname: Rasiah
authors.forename: Timothy
authors.initials: T
authors.lastname: Watts
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholl
authors.forename: Alison
authors.initials: A
authors.lastname: Bedford-Russell
authors.forename: Raoul
authors.initials: R
authors.lastname: Blumberg
authors.forename: Angela
authors.initials: A
authors.lastname: Thomas
authors.forename: Brenda
authors.initials: B
authors.lastname: Gibson
authors.forename: Chris
authors.initials: C
authors.lastname: Halsey
authors.forename: Pek-Wan
authors.initials: PW
authors.lastname: Lee
authors.forename: Sunit
authors.initials: S
authors.lastname: Godambe
authors.forename: Connor
authors.initials: C
authors.lastname: Sweeney
authors.forename: Neha
authors.initials: N
authors.lastname: Bhatnagar
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
authors.forename: Peter
authors.initials: P
authors.lastname: Campbell
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
mesh_terms: D000208:Acute Disease; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002999:Clone Cells / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D004314:Down Syndrome / Q000097:blood / Q000235:genetics*; D050982:GATA1 Transcription Factor; D005820:Genetic Testing / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D015997:Neonatal Screening / Q000379:methods; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D011289:Preleukemia / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D050982:GATA1 Transcription Factor
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