Somatic variant detection using an individual-specific pangenome reference: a case study of a pediatric acute myeloid leukemia patient

An individual-specific pangenome built from Nanopore assemblies in a pediatric acute myeloid leukemia case reduced pangenome-unique indel calls and removed three false-positive PRSS1 variants.

• Why it matters: Reference bias can produce false or missed somatic variant calls, including in clinically relevant genes, and pangenomes’ diagnostic value has been unclear.
• What they did: The study aligned bulk and single-cell short-read whole-genome sequencing to hg38 and to the individual-specific pangenome, anchored pangenome alignments to hg38, then called somatic variants with standard tools.
• The result: The pangenome supported detection of NUP98-NSD1 and FLT3-ITD, altered pangenome-based phylogeny branching, but also introduced surjection artifacts and structural-variant false positives requiring read-level inspection and validation.

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