title: GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.
abstract: BACKGROUND
  Children with Down syndrome (DS) are at increased risk of developing distinctive clonal myeloid disorders, including transient abnormal myelopoiesis (TAM) and myeloid leukaemia of DS (ML-DS). TAM connotes a spontaneously resolving congenital myeloproliferative state observed in 10%-20% of DS newborns. Following varying intervals of apparent remission, a proportion of children with TAM progress to develop ML-DS in early childhood. Therefore, TAM and ML-DS represent a biological continuum. Both disorders are characterised by recurring truncating somatic mutations of the GATA1 gene, which are considered key pathogenetic events.
  
  
  METHODS
  We herein report, to our knowledge, the first observation on the frequency and nature of GATA1 gene mutations in a cohort of Malaysian children with DS-associated TAM (n = 9) and ML-DS (n = 24) encountered successively over a period of five years at a national referral centre.
  
  
  RESULTS
  Of the 29 patients who underwent GATA1 analysis, GATA1 mutations were observed in 15 (51.7%) patients, including 6 (75.0%) out of 8 patients with TAM, and 9 (42.9%) of 21 patients with ML-DS. All identified mutations were located in exon 2 and the majority were sequence-terminating insertions or deletions (66.7%), including several hitherto unreported mutations (12 out of 15).
  
  
  CONCLUSIONS
  The low frequency of GATA1 mutations in ML-DS patients is unusual and potentially indicates distinctive genomic events in our patient cohort.
authors.affiliation: Department of Paediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Su Han
authors.initials: SH
authors.lastname: Lum
authors.affiliation: Department of Paediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Soo Sin
authors.initials: SS
authors.lastname: Choong
authors.affiliation: Department of Paediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia.|University Malaya Cancer Research Institute, Faculty of Medicine, Kuala Lumpur, Malaysia.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Unit of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Zulqarnain
authors.initials: Z
authors.lastname: Mohamed
authors.affiliation: Department of Paediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia.|University Malaya Cancer Research Institute, Faculty of Medicine, Kuala Lumpur, Malaysia.
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
mesh_terms: D015331:Cohort Studies; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D005091:Exons; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics*; D017353:Gene Deletion; D023281:Genomics; D006801:Humans; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000150:complications / Q000235:genetics*; D007955:Leukemoid Reaction / Q000150:complications / Q000235:genetics*; D008296:Malaysia; D008297:Male; D009154:Mutation; D012017:Referral and Consultation; D012074:Remission Induction
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human
keywords: Down syndrome; GATA1; ML-DS; TAM