title: Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus.
abstract: Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Chase
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: W
authors.initials: W
authors.lastname: Leung
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: W
authors.initials: W
authors.lastname: Tapper
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Jones
authors.affiliation: Hematology unit, Cliniques Universitaires Saint-Luc and de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Knoops
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Rasi
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: L A
authors.initials: LA
authors.lastname: Forsberg
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Zoi
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: V
authors.initials: V
authors.lastname: Hall
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.
authors.forename: L
authors.initials: L
authors.lastname: Chiecchio
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.
authors.forename: L
authors.initials: L
authors.lastname: Eder-Azanza
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bryant
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: L
authors.initials: L
authors.lastname: Docherty
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: H E
authors.initials: HE
authors.lastname: White
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Score
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: D J G
authors.initials: DJ
authors.lastname: Mackay
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: J P
authors.initials: JP
authors.lastname: Dumanski
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D019175:DNA Methylation; D059472:Exome / Q000235:genetics; D018392:Genomic Imprinting; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D024182:Uniparental Disomy / Q000235:genetics*