PEUTZ-JEGHERS-SYNDROME - CONFIRMATION OF LINKAGE TO CHROMOSOME 19P13.3 AND IDENTIFICATION OF A POTENTIAL 2ND LOCUS, ON 19Q13.4

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease with var iable expression and incomplete penetrance, characterized by mucocutan eous pigmentation and hamartomatous polyposis. Patients with PJS have increased frequency of gastrointestinal and extraintestinal malignanci es (ovaries, testes, and breast). In order to map the locus (or loci) associated with PJS, we performed a genomewide linkage analysis, using DNA polymorphisms in six families (two from Spain, two from India, on e from the United States, and one from Portugal) comprising a total of 93 individuals, including 39 affected and 48 unaffected individuals a nd 6 individuals with unknown status. During this study, localization of a PJS gene to 13p13.3 (around marker D19S886) had been reported els ewhere. For our families, marker D19S886 yielded a maximum LOD score o f 4.74 at a recombination fraction (theta) of .045; multipoint linkage analysis resulted in a LOD score of 7.51 for the interval between D19 S886 and 19pter. However, markers on 19q13.4 also showed significant e vidence for linkage. For example, D19S880 resulted in a maximum LOD sc ore of 3.8 at theta = .13. Most of this positive linkage was contribut ed by a single family, PJS07. These results confirm the mapping of a c ommon PJS locus on 19p13.3 but also suggest the existence, in a minori ty of families, of a potential second PJS locus, on 19q13.4. Positiona l cloning and characterization of the PJS mutations will clarify the g enetics of the syndrome and the implication of the gene(s) in the pred isposition to neoplasias.