MOSAIC UNIPARENTAL DISOMY IN BECKWITH-WIEDEMANN SYNDROME

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.