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...
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BMC
2025-08-01
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| Series: | Molecular Cytogenetics |
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| Online Access: | https://doi.org/10.1186/s13039-025-00710-x |
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| author | Aki Ishikawa Masahiro Gotoh Mineko Ushiama Hiromi Sakamoto Noriko Tanabe Tomoko Watanabe Hourin Cho Masayoshi Yamada Kokichi Sugano Kouya Shiraishi Makoto Hirata Teruhiko Yoshida Akihiro Sakurai |
| author_facet | Aki Ishikawa Masahiro Gotoh Mineko Ushiama Hiromi Sakamoto Noriko Tanabe Tomoko Watanabe Hourin Cho Masayoshi Yamada Kokichi Sugano Kouya Shiraishi Makoto Hirata Teruhiko Yoshida Akihiro Sakurai |
| author_sort | Aki Ishikawa |
| collection | DOAJ |
| description | 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. 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. Functional analysis experiments demonstrated that this variant suppresses normal splicing, and the clinical significance of the STK11 variant, which was initially considered a variant of “uncertain significance,” was reclassified as “likely pathogenic” based on functional analysis. The interpretation of U12-type intronic variants remains particularly challenging due to limited data and the absence of specific recommendations in existing guidelines [1, 2], and when segregation analysis is difficult, functional analysis from splicing assays is essential to provide accurate genetic diagnosis and information for clinical management. However, further familial segregation analysis and further validation of potential exon-skipping events are necessary to fully characterize the splicing impact of this variant. |
| format | Article |
| id | doaj-art-ad50c55b23af4a23b6dd0bb370c7df6a |
| institution | Kabale University |
| issn | 1755-8166 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cytogenetics |
| spelling | doaj-art-ad50c55b23af4a23b6dd0bb370c7df6a2025-08-24T11:52:14ZengBMCMolecular Cytogenetics1755-81662025-08-011811810.1186/s13039-025-00710-xClarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11Aki Ishikawa0Masahiro Gotoh1Mineko Ushiama2Hiromi Sakamoto3Noriko Tanabe4Tomoko Watanabe5Hourin Cho6Masayoshi Yamada7Kokichi Sugano8Kouya Shiraishi9Makoto Hirata10Teruhiko Yoshida11Akihiro Sakurai12Department of Medical Genetics and Genomics, School of Medicine, Sapporo Medical UniversityDepartment of Clinical Genomics, National Cancer Center Research InstituteDepartment of Clinical Genomics, National Cancer Center Research InstituteDepartment of Clinical Genomics, National Cancer Center Research InstituteDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Clinical Genomics, National Cancer Center Research InstituteDepartment of Genetic Medicine and Services, National Cancer Center HospitalDepartment of Clinical Genomics, National Cancer Center Research InstituteDepartment of Medical Genetics and Genomics, School of Medicine, Sapporo Medical UniversityAbstract 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. 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. Functional analysis experiments demonstrated that this variant suppresses normal splicing, and the clinical significance of the STK11 variant, which was initially considered a variant of “uncertain significance,” was reclassified as “likely pathogenic” based on functional analysis. The interpretation of U12-type intronic variants remains particularly challenging due to limited data and the absence of specific recommendations in existing guidelines [1, 2], and when segregation analysis is difficult, functional analysis from splicing assays is essential to provide accurate genetic diagnosis and information for clinical management. However, further familial segregation analysis and further validation of potential exon-skipping events are necessary to fully characterize the splicing impact of this variant.https://doi.org/10.1186/s13039-025-00710-xPeutz–jeghers syndromeSTK11Abnormal splicingGenetic analysisClinical relevanceU12-type intron |
| spellingShingle | Aki Ishikawa Masahiro Gotoh Mineko Ushiama Hiromi Sakamoto Noriko Tanabe Tomoko Watanabe Hourin Cho Masayoshi Yamada Kokichi Sugano Kouya Shiraishi Makoto Hirata Teruhiko Yoshida Akihiro Sakurai Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 Molecular Cytogenetics Peutz–jeghers syndrome STK11 Abnormal splicing Genetic analysis Clinical relevance U12-type intron |
| title | Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 |
| title_full | Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 |
| title_fullStr | Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 |
| title_full_unstemmed | Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 |
| title_short | Clarification of the clinical significance of an intron variant in a case of Peutz–Jeghers syndrome with abnormal RNA splicing of STK11 |
| title_sort | clarification of the clinical significance of an intron variant in a case of peutz jeghers syndrome with abnormal rna splicing of stk11 |
| topic | Peutz–jeghers syndrome STK11 Abnormal splicing Genetic analysis Clinical relevance U12-type intron |
| url | https://doi.org/10.1186/s13039-025-00710-x |
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