Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11

Abstract Peutz–Jeghers syndrome is an autosomal dominant disease characterized by intestinal polyposis, mucocutaneous pigmentation, and an increased risk of various types of cancer. Germline mutations in STK11 (LKB1), which encodes serine/threonine kinase 11, have been identified as the major cause of Peutz–Jeghers syndrome. Here, we detected a rare variant of undetermined significance in intron 2 of STK11 using multi-gene panel analysis in a girl with clinically suspected Peutz–Jeghers syndrome based on family history and characteristic mucocutaneous pigmentation. We confirmed this variant caused abnormal splicing in exons 2 and 3 using reverse transcription-PCR and Sanger sequencing. To validate the predicted impact of this variant on splicing, we performed functional analysis using a minigene assay. The functional analysis experiments demonstrated that this variant suppressed normal splicing, and the clinical significance of the STK11 variant, which was initially thought to be a variant of “Uncertain Significance,” was determined to be “Likely Pathogenic.” Functional analysis and confirming the genetic diagnosis of cases with actionable hereditary diseases would be helpful for surveillance decisions and family diagnosis.