The SINEs were there: identification of a pathogenic Alu insertion in a patient with DICER1-related tumour predisposition

Pathogenic Alu insertion in the RNase IIIa domain of *DICER1*, identified by long-read sequencing

This case reports a 14-year-old girl with multiple tumors suggestive of DICER1-related predisposition, but with no detectable germline variant by next-generation sequencing or short-read genome (only somatic hotspot DICER1 variants were found). Retrospective review of alignments revealed a consistent structural variant across all samples, suggesting an Alu element insertion in the RNase IIIa domain of DICER1. Long-read nanopore sequencing confirmed a pathogenic AluY insertion predicted to disrupt DICER1 function. This case illustrates the value of long-read sequencing for unmasking complex variants missed by conventional approaches.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A nice clinical illustration of long-read sequencing's contribution to resolving a “clinically obvious but genetically negative” case — a frustrating and frequent situation in pediatric cancer genetics. Mobile element (Alu) insertions are systematically missed by short-read and deserve consideration in a clear phenotype without a variant. Beyond the targeted panel, this demonstrates the value of a well-interpreted long-read genome for diagnostic confirmation and cascade family testing.