Long-read genome and RNA sequencing resolve a pathogenic intronic germline LINE-1 insertion in APC
Familial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the tumor suppressor gene APC. Confirmation of diagnosis was not achieved by cancer gene panel and exome sequencing or custom array-CGH in a family with suspected FAP across five generations. Long-read genome sequencing (PacBio), short-read genome sequencing (Illumina), short-read RNA sequencing, and further validations were performed in different tissues of multiple family members. Long-read genome sequencing resolved a 6 kb full-length intronic insertion of a heterozygous LINE-1 element between exons 7 and 8 of APC that could be detected but not fully resolved by short-read genome sequencing. Targeted RNA analysis revealed aberrant splicing resulting in the formation of a pseudo-exon with a premature stop codon. The variant segregated with the phenotype in several family members allowing its evaluation as likely pathogenic. This study supports the utility of long-read DNA sequencing and complementary RNA approaches to tackle unsolved cases of hereditary disease.
Authors
- Anja Richter
- Lisanne I Knol (ORCID: https://orcid.org/0000-0002-8975-0398)
- Stefan Aretz (ORCID: https://orcid.org/0000-0002-5228-1890)
- Arne Jahn (ORCID: https://orcid.org/0000-0003-1045-1908)
- Karl Hackmann (ORCID: https://orcid.org/0000-0003-4181-2120)
- Daniela Richter (ORCID: https://orcid.org/0009-0004-8958-140X)
- Marcus Franke
- Joseph Porrmann (ORCID: https://orcid.org/0000-0001-8474-6309)
- Isabel Spier (ORCID: https://orcid.org/0000-0003-2407-7427)
- Evelin Schröck (ORCID: https://orcid.org/0000-0002-3377-1704)
- Daniela Ellen Aust (ORCID: https://orcid.org/0000-0002-4867-8852)
- Thomas J. Widmann (ORCID: https://orcid.org/0000-0003-0544-7269)
- Hanno Glimm (ORCID: https://orcid.org/0000-0003-4104-1135)
- Anke Baumann (ORCID: https://orcid.org/0009-0003-8946-8741)
- Doreen William (ORCID: https://orcid.org/0000-0001-7824-5073)
- Sylke Winkler (ORCID: https://orcid.org/0000-0002-0915-3316)
- Tim Hutschenreiter (ORCID: https://orcid.org/0009-0007-6456-2108)
- M. Arlt
Institutions
- University of Bonn (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- Helmholtz-Zentrum Dresden-Rossendorf (DE)
- German Cancer Society (DE)
- National Center for Tumor Diseases (DE)
- Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- University Hospital Carl Gustav Carus (DE)
- Nationales Centrum für Tumorerkrankungen Dresden (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1038/s41525-025-00485-5
- Citations
- 4
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- European Commission
- Technische Universität Dresden