title: Mosaic segmental uniparental isodisomy and progressive clonal selection: a common mechanism of late onset β-thalassemia major.
abstract: Genomic DNA of 3 patients, born as healthy carriers and developing a late-onset severe transfusion-dependent beta-thalassemia major was studied by high-density genome wide SNP array analysis. A mosaic loss of heterozygosity for almost the entire 11p was found, not attributable to deletions but involving mosaicism for segmental paternal isodisomy of 11p. Mitotic recombination leading to mosaic segmental uniparental isodisomy on chromosome 11p in multiple tissues has been described as a molecular disease mechanism for a subset of sporadic Beckwith-Wiedemann syndrome cases. A similar mechanism also seems to be involved in causing late-onset disease in carriers of recessive mutations in other genes located in 11p, such as late-onset beta-thalassemia major and sickle cell disease. We suggest that the loss of maternally imprinted IGF-2 and H19 genes may account for the selective advantage of hematopoietic cells containing this segmental paternal isodisomy of 11p carrying the β-thalassemia mutation.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. c.l.harteveld@lumc.nl
authors.forename: Cornelis L
authors.initials: CL
authors.lastname: Harteveld
authors.forename: Chiara
authors.initials: C
authors.lastname: Refaldi
authors.forename: Antonino
authors.initials: A
authors.lastname: Giambona
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.forename: Mariëtte J V
authors.initials: MJ
authors.lastname: Hoffer
authors.forename: Jeroen
authors.initials: J
authors.lastname: Pijpe
authors.forename: Peter
authors.initials: P
authors.lastname: De Knijff
authors.forename: Caterina
authors.initials: C
authors.lastname: Borgna-Pignatti
authors.forename: Aurelio
authors.initials: A
authors.lastname: Maggio
authors.forename: Maria D
authors.initials: MD
authors.lastname: Cappellini
authors.forename: Piero C
authors.initials: PC
authors.lastname: Giordano
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000483:Alleles; D002648:Child; D002880:Chromosomes, Human, Pair 11; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy; D055815:Young Adult; D055544:beta-Globins / Q000235:genetics; D017086:beta-Thalassemia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D055544:beta-Globins