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.