POSITIONAL CLONING OF GENES INVOLVED IN THE BECKWITH-WIEDEMANN SYNDROME, HEMIHYPERTROPHY, AND ASSOCIATED CHILDHOOD TUMORS

The Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation sy ndrome that occurs with an incidence of 1:13,700 births. There is a st riking incidence of childhood tumors found in BWS patients. Various li nes of investigation have localized ''imprinted'' genes involved in BW S and associated childhood tumors to 11p15. High resolution mapping of 8 rare balanced chromosomal BWS rearrangements enabled us to identify three distinct regions on chromosome 11p15 that might harbor genes in volved in the above-mentioned disorders. These results suggest genetic heterogeneity that correlates with the clinical heterogeneity seen in the patients studied. Expressed candidate gene sequences from these r egions have been cloned and parity sequenced. These transcripts are ei ther disrupted by or are at least within a few kb of these BWS chromos ome breakpoints. So far, zinc-finger sequences and one Kruppel-associa ted box (KRAB) domain were found in independent candidate genes which are compatible with a regulating function of growth promoting genes. T he abundance of expression of these genes varies from low abundant in all adult and fetal tissues tested to detectable on Northern blots of adult tissues. In addition to our 11p15 studies we have analyzed addit ional chromosome regions, in particular 1p. Cytogenetic, loss of heter ozygosity (LOH) and comparative genomic hybridization (CGH) studies ha ve identified 1p35 as a region of interest. A positional cloning effor t to identify a balanced 1p35 translocation found in a Wilms tumor has led to the isolation of a YAC, crossing this breakpoint. (C) 1996 Wil ey-Liss, Inc.