Peutz-Jeghers Syndrome via the STK11 Gene

Peutz-Jeghers syndrome (PJS; OMIM 175200) is an autosomal dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and melanin pigmentation around the mouth, eyes, nostrils, buccal mucosa, fingers, toes, and other sites. PJS patients typically present in early childhood with pigmentation or with complications of polyposis, such as intussusception, bowel obstruction, or bleeding. Compared to the general population, patients with PJS have an increased risk of intestinal and various extra-intestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer; their lifetime risk is ~4 fold higher for gastrointestinal cancer and ~6 fold higher for breast cancer compared to individuals without PJS (Hearle et al. Clin Cancer Res 12:3209-3215, 2006). Approximately 75% of PJS cases are known to be familial while the remainder appears to be sporadic (Lim et al. Br. J Cancer 89:308-313, 2003).

Peutz-Jeghers syndrome is caused by heterozygous germline variants in the tumor suppressor gene STK11 (OMIM 602216). STK11, also called LKB1, consists of 9 exons and encodes a serine/threonine kinase that inhibits cellular proliferation by promoting cell-cycle arrest (Tiainen et al. PNAS 96:9248-9251, 1999). Second hit variants in STK11 ultimately lead to unfettered growth and tumorigenesis. To date, ~100 unique variants have been described throughout the STK11 gene (Human Gene Mutation Database, www.hgmd.cf.ac.uk). Most (80%) are truncating variants (i.e. frameshift, nonsense, splice-site, or exonic deletions) that result in early protein termination (Hearle et al. Clin Cancer Res 12:3209-3215, 2006). The remaining variants are missense or in-frame deletions. Large genomic deletions in STK11 have also been described.

Approximately 55% of patients with a positive family history or 70% of patients with no family history of Peutz-Jeghers syndrome will have a pathogenic variant detectable by sequencing (Amos et al. GeneReviews. 2011). Approximately 45% of patients with a positive family history or 21% of patients with no family history of Peutz-Jeghers syndrome will have a pathogenic variant detectable by deletion analysis (Amos et al. GeneReviews. 2011).

This test provides full coverage of all coding exons of the STK11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Deletion and duplication testing for STK11 is performed using NGS, but CNVs detected are confirmed via Multiplex Ligation-dependent Probe Amplification (MLPA).