Beckwith-Wiedemann syndrome (BWS) is an autosomal dominant disorder of
increased prenatal growth and predisposition to embryonal cancers suc
h as Wilms tumor. BWS is thought to involve One or more imprinted gene
s, since some patients show paternal uniparental disomy, and others sh
ow balanced germ-line chromosomal rearrangements involving the materna
l chromosome. We previously mapped BWS, by genetic linkage analysis, t
o 11p15.5, which are and others also found to contain several imprinte
d genes; these include the gene for insulin-like growth factor II (IGF
2) and H19, which show abnormal imprint-specific expression and/???? o
r methylation in 20% of BWS patients, and p57(KIP2), a cyclin-dependen
t Kinase inhibitor, which we found showed biallelic expression in one
of nine BWS patients studied. In addition, p57(KIP2) was recently repo
rted to show mutations ire two of nine BWS patients. We have now analy
zed the entire coding sequence and intronexon boundaries of p57(KIP2)
in 40 unrelated BWS patients. Of these patients, only two (5%) showed
mutations, both involving frameshifts in the second exon, In one case,
the mutation was transmitted to the proband's mother, who was also af
fected, from the maternal grandfather, suggesting that p57(KIP2) is no
t: imprinted in at least some affected tissues at a critical stage of
development and that haploinsufficiency due to mutation of either pare
ntal allele may cause at least some features of BWS. The low frequency
of p57(KIP2) mutations, as well as our recent discovery of disruption
of the K(v)LQT1 gene in patients with chromosomal rearrangements, sug
gest that BWS can involve disruption of multiple independent 11p15.5 g
enes.