Cloning of translocation breakpoints associated with Shwachman syndrome and identification of a candidate gene

Shwachman syndrome is an autosomal-recessive disorder characterized by exoc rine pancreatic insufficiency, bone-marrow dysfunction, and metaphyseal cho ndrodysplasia. A de novo balanced translocation was recently documented in a patient with this disease. Toward isolating the gene(s) responsible for S hwachman syndrome, we cloned and sequenced the translocation breakpoints in the DNA of this patient. The nucleotide sequences around the breakpoints c ontained neither repetitive elements nor motifs reported to be implicated i n recombination events, although we did detect gains or losses of oligonucl eotides at the translocation junctions. By large-scale genomic sequencing a nd in silico gene trapping. we identified two novel transcripts in the vici nity of the breakpoints that might represent candidate genes for Shwachman syndrome, one on chromosome 6 and the other on chromosome 12. The gene on c hromosome 12 was actually disrupted by the translocation.