Inherited and Sporadic Epimutations at the <i>IGF2-H19</i> Locus in Beckwith-Wiedemann Syndrome and Wilms&rsquo; 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.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

“…The following molecular anomalies were identified: 190 IC2-LoM (184 epigenetic anomalies, 5 already published cases with familial IC2 duplications 21 and 1 IC2 deletion), 87 UPD carriers, 31 IC1-GoM (21 already published cases 22,23 including one IC1 duplication, one translocation, 11 familial microdeletions [24][25][26] ), 10 CDKN1C variants (all unrelated cases, 9 maternally inherited). None of the patients tested was positive for genome-wide UPD.…”

Longitudinal epigenetic drift in mice perinatally exposed to lead

“…As with Cabp IAP , in control mice there was no statistically significant increase in DNA methylation from day 22 to 10 mo; however, in mice from every level of lead exposure, the absolute methylation level increased significantly (all P < 0.05). 38 Linking methylation to physiological change, Huang et al 39 found an association with DNA methylation at the human IGF2/H19 imprinting control region (ICR) and subcutaneous fat but not with BMI in adolescents. They hypothesize that peripheral fat deposits are influenced by IGF2/ H19 ICR methylation in early life obesogenic environments.…”

Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects

“…As methylation is a key regulator of imprinted gene expression, methylation disturbances at DMRs have been associated with many congenital growth disorders. 14 Research has shown that the methylation patterns of imprinted genes are sensitive to malnutrition in early embryonic development. 15 Despite the increased understanding of birth defects, the mechanism underlying the formation of NTDs remains unclear.…”