High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome

Germline mutations in the STK11 gene have been identified in 10-70% of patients with Peutz-Jeghers syndrome (PJS), an autosomal-dominant hamartomatous polyposis syndrome. A second locus was assumed in a large proportion of PJS patients. To date, STK11 alterations comprise mainly point mutations; only a small number of large deletions have been reported. We performed a mutation analysis for the STK11 gene in 71 patients. Of these, 56 met the clinical criteria for PJS and 12 were presumed to have PJS because of mucocutaneous pigmentation only or bowel problems due to isolated PJS polyps. No clinical information was available for the remaining three patients. By direct sequencing of the coding region of the STK11 gene, we identified point mutations in 37 of 71 patients (52%). We examined the remaining 34 patients by means of the multiplex ligation-dependent probe amplification (MLPA) method, and detected deletions in 17 patients. In four patients the deletion extended over all 10 exons, and in eight patients only the promoter region and exon 1 were deleted. The remaining deletions encompassed exons 2-10 (in two patients), exons 2-3, exons 4-5, or exon 8. When only patients who met the clinical criteria for PJS are considered, the overall mutation detection rate increases to 94% (64% point mutations and 30% large deletions). No mutation was identified in any of the 12 presumed cases. In conclusion, we found that approximately one-third of the patients who met the clinical PJS criteria exhibited large genomic deletions that were readily detectable by MLPA. Screening for point mutations and large deletions by direct sequencing or MLPA, respectively, increased the mutation detection rate in the STK11 gene up to 94%. There may be still other mutations in the STK11 gene that are not detectable by the methods applied here. Therefore, it is questionable whether a second PJS locus exists at all.