title: 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment.
abstract: Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental γ-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA;
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: Centro di Riferimento Regionale Genetica Medica, Azienda Ospedaliera-Universitaria di Perugia, Perugia, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
authors.affiliation: Genetica Medica, IRCCS "Ospedale Casa Sollievo della Sofferenza," San Giovanni Rotondo, Foggia, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Ottaviani
authors.affiliation: Dipartimento Scienze per la Promozione della Salute e Materno-Infantile "G. D'Alessandro," Università degli Studi di Palermo, Palermo, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Piccione
authors.affiliation: Unità Operative Complesse di Ematologia delle Malattie Rare del Sangue e degli Organi Emopoietici, Palermo, Italy;
authors.forename: Antonino
authors.initials: A
authors.lastname: Giambona
authors.affiliation: Unità Operative Complesse di Ematologia delle Malattie Rare del Sangue e degli Organi Emopoietici, Palermo, Italy;
authors.forename: Aurelio
authors.initials: A
authors.lastname: Maggio
authors.affiliation: Department of Biologia Cellulare and Neuroscience, Istituto Superiore Sanita, Rome, Italy;
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ciaffoni
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA;
authors.forename: Sandra
authors.initials: S
authors.lastname: Stehling-Sun
authors.affiliation: Department of Biologia Cellulare and Neuroscience, Istituto Superiore Sanita, Rome, Italy;
authors.forename: Manuela
authors.initials: M
authors.lastname: Marra
authors.affiliation: Department of Biologia Cellulare and Neuroscience, Istituto Superiore Sanita, Rome, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Masiello
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY;
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA; Division of Oncology, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY; Department of Biomedical Sciences, University of Bologna, Bologna, Italy; and.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Migliaccio
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism*; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000097:blood / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D015854:Up-Regulation
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005319:Fetal Hemoglobin