Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects

Am J Hum Genet. 2002 Mar;70(3):604-11. doi: 10.1086/338934. Epub 2002 Jan 28.


Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P=.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P=.012 and P=.02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P=.003), cancer (P=.03), and hypoglycemia (P=.05). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abdomen / abnormalities
  • Beckwith-Wiedemann Syndrome / complications*
  • Beckwith-Wiedemann Syndrome / genetics*
  • Beckwith-Wiedemann Syndrome / pathology
  • Chromosomes, Human, Pair 11 / genetics
  • Cohort Studies
  • DNA Methylation*
  • Female
  • Fetal Macrosomia / genetics
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genomic Imprinting
  • Humans
  • Hypertrophy / complications
  • Hypertrophy / genetics
  • Hypoglycemia / complications
  • Hypoglycemia / genetics
  • Male
  • Membrane Proteins*
  • Molecular Sequence Data
  • Neoplasms / complications*
  • Neoplasms / genetics*
  • Phenotype
  • Potassium Channels, Voltage-Gated
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics*
  • Registries
  • Uniparental Disomy / genetics


  • H19 long non-coding RNA
  • KCNQ1OT1 long non-coding RNA, human
  • Membrane Proteins
  • Potassium Channels, Voltage-Gated
  • RNA, Long Noncoding
  • RNA, Untranslated

Associated data

  • GENBANK/AA155639
  • OMIM/103280
  • OMIM/130650
  • OMIM/147470
  • OMIM/192500
  • OMIM/600856
  • OMIM/604115