DICER1-related tumour predisposition (DRTP) is an autosomal dominant disorder marked by increased risk of benign and malignant tumours across multiple organ systems. A genetic diagnosis of DRTP requires identification of a (likely) pathogenic germline DICER1 variant to confirm the diagnosis, and guide clinical management, including cascade testing and surveillance of at-risk relatives.
We report a 14-year-old girl who developed multiple DICER1-associated tumours with high clinical suspicion of DRTP. Initial testing via next-generation sequencing and whole genome sequencing revealed only hotspot somatic DICER1 variants, with no detectable germline variant, complicating the genetic diagnosis.
A structural variant (SV) initially detected in a tumour sample prompted retrospective review of alignment data from all previously tested tumour, blood and normal tissue samples. This revealed a consistent SV across all samples. Short-read data suggested the SV was an Alu element insertion within the RNase IIIa domain of DICER1, but read length was insufficient for conclusive characterisation.
Subsequent long-read nanopore sequencing confirmed a pathogenic AluY insertion, predicted to disrupt DICER1 function.
This case highlights the importance of comprehensive genomic and functional analyses, especially in unresolved cases with strong clinical suspicion. It also demonstrates the value of long-read sequencing in identifying complex variants missed by conventional approaches.