title: Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia.
abstract: The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Harriet
authors.initials: H
authors.lastname: Holme
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Upal
authors.initials: U
authors.lastname: Hossain
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Walne
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, UK.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D000090243:Nucleophosmin; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin