Inherited and sporadic epimutations at the IGF2-H19 locus in beckwith-wiedemann syndrome and wilms' tumor

Andrea Riccio, Angela Sparago, Gaetano Verde, Agostina De Crescenzo, Valentina Citro, Maria Vittoria Cubellis, Giovanni Battista Ferrero, Margherita Cirillo Silengo, Silvia Russo, Lidia Larizza, Flavia Cerrato

Research output: Chapter in Book/Report/Conference proceedingConference contribution


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.

Original languageEnglish
Title of host publicationEndocrine Development
Number of pages9
Publication statusPublished - 2009

Publication series

NameEndocrine Development
ISSN (Print)14217082
ISSN (Electronic)16622979

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Pediatrics, Perinatology, and Child Health
  • Endocrinology
  • Endocrine and Autonomic Systems


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