Optical genome mapping enhanced by refined variant interpretation in pediatric acute lymphoblastic leukemia.

Genome-wide detection of structural variants and copy number variations by optical genome mapping, with copy number values normalised by DNA index and a dedicated evaluation of variant fringe zones, applied in particular to complex translocations involving ETV6::RUNX1 and KMT2A.

Reliable detection of structural variants and copy number variations underpins the diagnosis of paediatric B-cell acute lymphoblastic leukaemia (B-ALL), yet conventional and molecular cytogenetic methods limit accurate characterisation. The authors screened 51 children with B-ALL using optical genome mapping (OGM) and compared results with karyotyping, FISH, digitalMLPA and targeted RNA sequencing. OGM showed high congruency with karyotyping and FISH, detected clinically relevant variants beyond G-banding and resolved a complex KMT2A fusion missed by FISH. Normalising copy number values by DNA index improved concordance with FISH-derived copy numbers in near-tri/tetraploid cases, and a new strategy for evaluating variant fringe zones, FriZone, significantly improved concordance between OGM and digitalMLPA; a co-segregation analysis also showed strong associations between the ETV6::RUNX1 fusion and deletions of ETV6, RAG2 and NR3C2. Overall, OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of patients.

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

The useful message is not OGM itself, already well documented in haematological malignancies, but the fact that its yield depends on interpretation: without DNA-index normalisation, near-tri/tetraploid cases — common in paediatric B-ALL — remain poorly quantified. The 10% of patients whose risk stratification changes is the figure to remember, with the caveat of a single-centre series of 51 children and an unblinded comparison with reference methods. FriZone remains an in-house heuristic that will need external replication before entering an accredited protocol.

Analysis by Dr Thibaut Benquey