Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome
with variable expression. The major features are anterior abdominal wa
ll defects, macroglossia, and gigantism and less commonly neonatal hyp
oglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy
and embryonal tumours occur. BWS is a genetically heterogeneous disord
er; most cases are sporadic but approximately 15% are familial and a s
mall number of BWS patients have cytogenetic abnormalities involving c
hromosome 11p15. Genomic imprinting effects have been implicated in fa
milial and non-familial BWS, and uniparental disomy (UPD) for chromoso
me 11 has been reported in sporadic cases. We investigated the inciden
ce, pathogenesis, and clinical associations of UPD in 49 patients with
non-familial BWS and a normal karyotype. UPD for chromosome 11p15 was
detected in nine of 32 (28%) informative patients. A further two pati
ents appeared to be disomic at the WT1 locus in chromosome 11p13, but
were uninformative at chromosome 11p15.5 loci tested. In all cases wit
h UPD the affected person was mosaic for a paternal isodisomy and a no
rmal cell line indicating that UPD had arisen as a postzygotic event.
Compared to cases in which paternal isodisomy for chromosomes 11p15.5
had been excluded (n = 23), BWS patients with UPD was more likely to h
ave hemihypertrophy (6/9 versus 1/23, p<0.001) and less likely to have
exomphalos (0/9 versus 13/23, p<0.01), but there were no significant
differences between disomic and non-disomic cases in the incidence of
hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The d
etection of UPD in BWS patients allows accurate genetic counselling to
be provided and provides an insight into the molecular pathogenesis o
f BWS.