title: Inherited and Sporadic Epimutations at the IGF2-H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumor.
abstract: The parent-of-origin-dependent expression of IGF2 and H19 is controlled by the imprinting center 1 (IC1) consisting of a methylation-sensitive chromatin insulator. IC1 is normally methylated on the paternal chromosome and nonmethylated on the maternal chromosome. We found that 22 cases in a large cohort of patients affected by Beckwith-Wiedemann syndrome (BWS) had IC1 methylated on both parental chromosomes, resulting in biallelic activation of IGF2 and biallelic silencing of H19. These individuals had marked macrosomia and high incidence of Wilms' tumor. A subset of these patients had 1.4- to 1.8-kb deletions with hypermethylation of the remaining IC1 region and fully penetrant BWS phenotype when transmitted maternally. Another subset of individuals with IC1 hypermethylation had a similar clinical phenotype but no mutation in the local vicinity. All these cases were sporadic and in at least two families affected and unaffected members shared the same maternal IC1 allele but not the abnormal maternal epigenotype. Similarly, no IC1 deletion was detected in 10 nonsyndromic Wilms' tumors with IC1 hypermethylation. In conclusion, methylation defects at the IGF2-H19 locus can result from inherited mutations of the imprinting center and have high recurrence risk or arise independently from the sequence context and not transmitted to the progeny.
authors.affiliation: Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Caserta, Italy. andrea.riccio@unina2.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
authors.forename: Angela
authors.initials: A
authors.lastname: Sparago
authors.forename: Gaetano
authors.initials: G
authors.lastname: Verde
authors.forename: Agostina
authors.initials: A
authors.lastname: De Crescenzo
authors.forename: Valentina
authors.initials: V
authors.lastname: Citro
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.forename: Flavia
authors.initials: F
authors.lastname: Cerrato
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II