Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1381 |
| _version_ | 1827345749317255168 |
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| author | Thorkild Terkelsen Ole H. Larsen Søren Vang Uffe B. Jensen Friedrik Wikman |
| author_facet | Thorkild Terkelsen Ole H. Larsen Søren Vang Uffe B. Jensen Friedrik Wikman |
| author_sort | Thorkild Terkelsen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T23:17:07Z |
| format | Article |
| id | doaj.art-91e31e77595f4b7f98258d8430790a7a |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:17:07Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-91e31e77595f4b7f98258d8430790a7a2024-02-21T10:24:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-09-0189n/an/a10.1002/mgg3.1381Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron fiveThorkild Terkelsen0Ole H. Larsen1Søren Vang2Uffe B. Jensen3Friedrik Wikman4Department of Clinical Genetics Aarhus University Hospital Aarhus DenmarkDepartment of Molecular Medicine Aarhus University Hospital Aarhus DenmarkDepartment of Molecular Medicine Aarhus University Hospital Aarhus DenmarkDepartment of Clinical Genetics Aarhus University Hospital Aarhus DenmarkDepartment of Molecular Medicine Aarhus University Hospital Aarhus DenmarkAbstract 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.https://doi.org/10.1002/mgg3.1381germline mutationLKB1Peutz–Jeghers syndromeRNA‐Seqsplice variantSTK11 |
| spellingShingle | Thorkild Terkelsen Ole H. Larsen Søren Vang Uffe B. Jensen Friedrik Wikman Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five Molecular Genetics & Genomic Medicine germline mutation LKB1 Peutz–Jeghers syndrome RNA‐Seq splice variant STK11 |
| title | Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five |
| title_full | Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five |
| title_fullStr | Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five |
| title_full_unstemmed | Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five |
| title_short | Deleterious mis‐splicing of STK11 caused by a novel single‐nucleotide substitution in the 3′ polypyrimidine tract of intron five |
| title_sort | deleterious mis splicing of stk11 caused by a novel single nucleotide substitution in the 3 polypyrimidine tract of intron five |
| topic | germline mutation LKB1 Peutz–Jeghers syndrome RNA‐Seq splice variant STK11 |
| url | https://doi.org/10.1002/mgg3.1381 |
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