Patients with heterozygous deletions of the long arm of chromosome 13 have a variable phenotype that depends upon the deleted segment and ranges from mild mental retardation and minor dysmorphic features to major malformations which are usually lethal in early life (the """"""""13q-""""""""syndrome). We have preliminary evidence that the deletion of a small (less than 1 megabase) region in band q32 results in the severe phenotype, typiCally involving malformations of the brain, heart, kidneys and digits. The long term goal of this project is to isolate and characterize the developmentally important gene or genes which we hypothesize are present in this region. This will be accomplished through the following specific aims: 1. Define the critical region in chromosome 13q. We will continue to use patient derived cell lines to define the minimal common region of deletion in patients with 13q deletions who have the severe,phenotype. Simultaneously, we will construct YAC, cosmid and PI contigs of this """"""""critical region'. 2. Isolate and sequence genes within the critical region. Exon amplification as well as a new method of subtractive hybridization which we have developed at our institution will be used to isolate genes which are located in the critical region. 3. Select candidate genes. Genes likely to have a role in the developmental processes which are disrupted in the 13q syndrome patients will be selected by homology searches as well as studies of the tissue distribution and timing of expression by Northern and by in situ hybridization analysis. 4. Isolate and characterize murine homologues of candidate cDNAs. The murine homologues of candidate genes will be isolated, and the timing and tissue distribution of their expression will be investigated. The syntenic region of the mouse genome will be identified and examined for possible similar developmental mutants. 5. Look for microdeletions in patients with isolated holoprosencephaly. PCR with a collection of highly polymorphic markers from within the critical region will be used to screen for microdeletions in patients with isolated holoprosencephaly. DNA samples from such patients and their parents will be made available to us through a collaboration.
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