We describe a family in whom the phenotypically normal father carries a balanced insertional translocation, ins(14;11)(q23;p12p14). This individual fathered three mentally retarded children, two with a del(11)(p13) and one with a dup(11)(p13). Two other cases of a de novo del(11)(p13) are also described. All four del(11)(pl3) cases presented with WAGR, a complex syndrome associated with a predisposition to Wilms’ tumor (WT), aniridia (A), genitourinary abnormalities (G), and mental retardation (R). Using an approach combining karyotype analysis, determination of the gene copy number, and RFLP studies employing five 11p13 DNA markers, we were able to define the chromosomal rearrangement involved in each case. Analysis of these WAGR deletions provides further subdivision of band p13 on chromosome 11.

Gene expression for the four different growth-regulatory proteins for cells of the myeloid hematopoietic cell lineages was analyzed in mouse fetal and extraembryonic tissues at various stages of development. The macrophage growth inducer MGI-1M (colony-stimulating factor 1) was the only myeloid hematopoietic growth regulator detected as both mRNA and bioactive protein during fetal development. This regulator was produced predominantly in extraembryonic tissues, and the production of hematopoietic growth regulators in embryogenesis was regulated by transcriptional and posttranscriptional controls.

Most patients with the complex association aniridia - predisposition to Wilms' tumor (WAGR syndrome) present with a de novo constitutional deletion of band 11p13. We report a patient with WAGR syndrome and a reciprocal translocation between chromosomes 5 and 11 t(5;11) (q11;p13). High resolution banding cytogenetic analysis and molecular characterization using 11p13 DNA markers showed a tiny deletion encompassing the gene for CAT but sparing the gene for FSHB. This suggests that syndromes associated with apparently balanced translocations may be due to undetectable loss of material at the breakpoint(s) rather than to breakage in the gene itself.

The short arm of chromosome 11 carries genes involved in malformation syndromes, including the aniridia/genitourinary abnormalities/mental retardation (WAGR) syndrome and the Beckwith-Wiedemann syndrome, both of which are associated with an increased risk of childhood malignancy. Evidence comes from constitutional chromosomal aberrations and from losses of heterozygosity, limited to tumor cells, involving regions 11p13 and 11p15. In order to map the genes involved more precisely, we have fused a mouse cell line with cell lines from patients with constitutional deletions or translocations. Characterization of somatic cell hybrids with 11p-specific DNA markers has allowed us to subdivide the short arm into 11 subregions, 7 of which belong to band 11p13. We have thus defined the smallest region of overlap for the Wilms' tumor locus bracketed by the closest proximal and distal breakpoints in two of these hybrids. The region associated with the Beckwith-Wiedemann syndrome spans the region flanked by two 11p15.5 markers, HRAS1 and HBB. These hybrids also represent useful tools for mapping new markers to this region of the human genome.