TY  - JOUR
AU  - Baumann, Alexandra A
AU  - Knol, Lisanne I
AU  - Arlt, Marie
AU  - Hutschenreiter, Tim
AU  - Richter, Anja
AU  - Widmann, Thomas J
AU  - Franke, Marcus
AU  - Hackmann, Karl
AU  - Winkler, Sylke
AU  - Richter, Daniela
AU  - Spier, Isabel
AU  - Aretz, Stefan
AU  - Aust, Daniela
AU  - Porrmann, Joseph
AU  - William, Doreen
AU  - Schröck, Evelin
AU  - Glimm, Hanno
AU  - Jahn, Arne
TI  - Long-read genome and RNA sequencing resolve a pathogenic intronic germline LINE-1 insertion in APC.
JO  - npj Genomic Medicine
VL  - 10
IS  - 1
SN  - 2056-7944
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-00709
SP  - 30
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40180948
DO  - DOI:DOI:10.1038/s41525-025-00485-5
UR  - https://inrepo02.dkfz.de/record/300248
ER  -