EXCESS FUNCTIONAL COPY OF ALLELE AT CHROMOSOMAL REGION 11P15 MAY CAUSE WIEDEMANN-BECKWITH (EMG) SYNDROME

Wiedemann-Beckwith syndrome (WBS) is a genetic disorder with overgrowt h and predisposition to Wilms' tumor. The putative locus of the gene r esponsible for this syndrome is assigned to chromosome region 11p15.5, and genomic imprinting in this region has been proposed: the paternal ly derived gene(s) at 11p15.5 is selectively expressed, while the mate rnally transmitted gene(s) is inactive. We examined 18 patients for th e parental origin of their 11p15 regions. DNA polymorphism analyses us ing 6 loci on chromosome 11 showed that 2 patients with duplications o f 11p15 regions from their respective fathers and one from the mother, indicating the transmission of an excessive paternal gene at 11p15 to each patient. Our results, together with the previous findings in kar yotypically normal or abnormal patients and in overgrowth mouse experi ments, are consistent with imprinting hypothesis that overexpression o f paternally derived gene(s) at 11p15.5, probably the human insulin-li ke growth factor II (ICE-II) gene, may cause the phenotype. Total cons titutional uniparental paternal disomy (UPD) or segmental UPD for the 6 loci examined of chromosome 11 was not observed in our 12 sporadic p atients. In order to explain completely the inheritance of this syndro me in patients with various chromosomal constitutions, we propose an a lternative imprinting mechanism involving the other locus that may be paternally imprinted and may suppress the expression of this gene. (C) 1994 Wiley-Liss, Inc.