Deleterious mis-splicing of STK11 caused by a novel single-nucleotide substitution in the 3' polypyrimidine tract of intron five

Thorkild Terkelsen*, Ole H Larsen, Søren Vang, Uffe B Jensen, Friedrik Wikman

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

2 Citations (Scopus)
126 Downloads (Pure)

Abstract

BACKGROUND: Pathogenic variants in STK11, also designated as LKB1, cause Peutz-Jeghers syndrome, which is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation changes, polyposis, and a high risk of cancer.

METHODS: A male meeting the clinical diagnostic criteria for Peutz-Jeghers syndrome underwent next-generation sequencing. To validate the predicted splicing impact of a detected STK11 variant, we performed RNA-Seq on mRNA extracted from patient-derived Epstein-Barr virus-transformed lymphocytes treated with cycloheximide to inhibit nonsense-mediated decay ex vivo.

RESULTS: Blood testing identified a novel single-nucleotide substitution, NM_000455.4:c.735-10C>A, at the end of the 3' polypyrimidine tract of intron five in STK11. RNA-Seq confirmed a predicted eight base pair insertion in the mRNA transcript. Following inhibition of nonsense-mediated decay, the out-of-frame insertion was detected in 50% of all RNA-Seq reads. This confirmed a strong, deleterious splicing impact of the variant.

CONCLUSION: We characterized a novel likely pathogenic germline variant in intron five of STK11 associated with Peutz-Jeghers syndrome. The study highlights RNA-Seq as a useful supplement in hereditary cancer predisposition testing.

Original languageEnglish
Article numbere1381
JournalMolecular Genetics & Genomic Medicine
Volume8
Issue9
Number of pages6
ISSN2324-9269
DOIs
Publication statusPublished - 1 Sept 2020

Keywords

  • LKB1
  • Peutz–Jeghers syndrome
  • RNA-Seq
  • STK11
  • germline mutation
  • splice variant

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