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However, limitations of commonly used conventional and molecular cytogenetic methods may hinder the accurate genetic characterization of patients. Optical genome mapping (OGM) offers a reliable alternative by enabling high\u2010resolution, genome\u2010wide detection of CNVs and SVs. Chromosomal aberrations were screened using OGM in 51 children with B\u2010ALL. The results were compared with those of karyotyping, fluorescence\n in situ<\/jats:italic>\n hybridization (FISH), digital multiplex ligation\u2010dependent probe amplification (digitalMLPA), and targeted RNA sequencing (RNA\u2010seq). OGM data showed high congruency with karyotyping and FISH findings, detecting clinically relevant variants beyond G\u2010banding results and unraveling a complex\n KMT2A<\/jats:italic>\n fusion undetected by FISH. Gene fusions involved in complex\n ETV6<\/jats:italic>\n ::\n RUNX1<\/jats:italic>\n translocations, but not detected by RNA\u2010seq, were confirmed using FISH. Normalization of OGM copy number values with DNA\u2010index\u2010improved concordance with FISH\u2010derived copy numbers in near\u2010tri\/tetraploid cases. In the peripheral regions of OGM variants (fringe\u2010zones), a novel evaluation strategy called \u2018\n FriZone<\/jats:italic>\n \u2019 was applied, which significantly improved the concordance between OGM and digitalMLPA. In addition, a co\u2010segregation analysis revealed strong associations between\n ETV6<\/jats:italic>\n ::\n RUNX1<\/jats:italic>\n fusion and deletions of\n ETV6<\/jats:italic>\n ,\n RAG2<\/jats:italic>\n , and\n NR3C2<\/jats:italic>\n . OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of the patients. The\n FriZone<\/jats:italic>\n analysis and normalization by DNA\u2010index provide a refined, more accurate approach to OGM variant interpretation, facilitating the efficient application of OGM in clinical diagnostics. \u00a9 2026 The Author(s).\n The Journal of Pathology<\/jats:italic>\n published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n <\/jats:p>","DOI":"10.1002\/path.70096","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T06:03:18Z","timestamp":1785996198000},"page":"241-254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optical genome mapping enhanced by refined variant interpretation in pediatric acute lymphoblastic 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