Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome
Abstract Multigene panel tests (MGPTs) revolutionized the diagnosis of Lynch syndrome (LS), however noncoding pathogenic variants (PVs) can only be detected by complementary methods including whole genome sequencing (WGS). Here we present a DNA-, RNA- and tumor tissue-based WGS prioritization workfl...
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Nature Portfolio
2025-01-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-025-00461-z |
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| author | Klaudia Horti-Oravecz Anikó Bozsik Tímea Pócza Ildikó Vereczkey Tamás Strausz Erika Tóth Tatiana Sedlackova Diana Rusnakova Tomas Szemes István Likó Edit Oláh Henriett Butz Attila Patócs János Papp Vince Kornél Grolmusz |
| author_facet | Klaudia Horti-Oravecz Anikó Bozsik Tímea Pócza Ildikó Vereczkey Tamás Strausz Erika Tóth Tatiana Sedlackova Diana Rusnakova Tomas Szemes István Likó Edit Oláh Henriett Butz Attila Patócs János Papp Vince Kornél Grolmusz |
| author_sort | Klaudia Horti-Oravecz |
| collection | DOAJ |
| description | Abstract Multigene panel tests (MGPTs) revolutionized the diagnosis of Lynch syndrome (LS), however noncoding pathogenic variants (PVs) can only be detected by complementary methods including whole genome sequencing (WGS). Here we present a DNA-, RNA- and tumor tissue-based WGS prioritization workflow for patients with a suspicion of LS where MGPT detected no LS-related PV. Among the 100 enrolled patients, MGPT detected 28 simple PVs and an additional 3 complex PVs. Among the 69 MGPT-negative patients, the lack of somatic MLH1 promoter methylation in a patient with a distinguished MLH1 allelic imbalance selected this sample for WGS. This returned a germline deep intronic MLH1 variant, with further functional studies confirming its’ pathogenicity. Interestingly, all three complex PVs and the MLH1 deep intronic PV were found to be recurrent at our center. Our straightforward and cost-effective prioritization workflow can optimally include WGS in the genetic diagnosis of LS. |
| format | Article |
| id | doaj-art-81ad08d9b211470394f8abb71452ce20 |
| institution | Kabale University |
| issn | 2056-7944 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj-art-81ad08d9b211470394f8abb71452ce202025-01-19T12:33:35ZengNature Portfolionpj Genomic Medicine2056-79442025-01-0110111710.1038/s41525-025-00461-zWhole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndromeKlaudia Horti-Oravecz0Anikó Bozsik1Tímea Pócza2Ildikó Vereczkey3Tamás Strausz4Erika Tóth5Tatiana Sedlackova6Diana Rusnakova7Tomas Szemes8István Likó9Edit Oláh10Henriett Butz11Attila Patócs12János Papp13Vince Kornél Grolmusz14Department of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyDepartment of Surgical and Molecular Pathology, National Institute of OncologyDepartment of Surgical and Molecular Pathology, National Institute of OncologyNational Tumorbiology Laboratory, National Institute of OncologyComenius University Science ParkComenius University Science ParkComenius University Science ParkHereditary Tumors Research Group, HUN-REN – Semmelweis UniversityDepartment of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyDepartment of Molecular Genetics, National Institute of OncologyAbstract Multigene panel tests (MGPTs) revolutionized the diagnosis of Lynch syndrome (LS), however noncoding pathogenic variants (PVs) can only be detected by complementary methods including whole genome sequencing (WGS). Here we present a DNA-, RNA- and tumor tissue-based WGS prioritization workflow for patients with a suspicion of LS where MGPT detected no LS-related PV. Among the 100 enrolled patients, MGPT detected 28 simple PVs and an additional 3 complex PVs. Among the 69 MGPT-negative patients, the lack of somatic MLH1 promoter methylation in a patient with a distinguished MLH1 allelic imbalance selected this sample for WGS. This returned a germline deep intronic MLH1 variant, with further functional studies confirming its’ pathogenicity. Interestingly, all three complex PVs and the MLH1 deep intronic PV were found to be recurrent at our center. Our straightforward and cost-effective prioritization workflow can optimally include WGS in the genetic diagnosis of LS.https://doi.org/10.1038/s41525-025-00461-z |
| spellingShingle | Klaudia Horti-Oravecz Anikó Bozsik Tímea Pócza Ildikó Vereczkey Tamás Strausz Erika Tóth Tatiana Sedlackova Diana Rusnakova Tomas Szemes István Likó Edit Oláh Henriett Butz Attila Patócs János Papp Vince Kornél Grolmusz Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome npj Genomic Medicine |
| title | Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome |
| title_full | Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome |
| title_fullStr | Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome |
| title_full_unstemmed | Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome |
| title_short | Whole genome sequencing completes the molecular genetic testing workflow of patients with Lynch syndrome |
| title_sort | whole genome sequencing completes the molecular genetic testing workflow of patients with lynch syndrome |
| url | https://doi.org/10.1038/s41525-025-00461-z |
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